USPTO Patents Application 09993647

co-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors

Field of the Invention

This invention relates to the use of a group of aryl ureas in treating raf mediated diseases,
and pharmaceutical compositions for use in such therapy.

Background of the Invention

The p21 ras oncogene is a major contributor to the development and progression of human
solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann. Rep. Med.
Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, unmutated
form, the ras protein is a key element of the signal transduction cascade directed by
growth factor receptors in almost all tissues (Avruch et al. Trends Biochem. Set. 1994, 19,
279-83). Biochemically, ras is a guanine nucleotide binding protein, and cycling between
a GTP-bound activated and a GDP-bound resting form" is stricdy controlled by ras'
endogenous GTPase activity and other regulatory proteins. In the ras mutants in cancer
cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers
constitutive growth signals to downstream effectors such as the enzyme raf kinase. This
leads to the cancerous growth of the cells which carry these mutants (Magnuson et al.
Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibiting the effect of
active ras by inhibiting the raf kinase signaling pathway by administration of deactivating
antibodies to raf kinase or by co-expression of dominant negative raf kinase or dominant
negative MEK, the substrate of raf kinase, leads to the reversion of transformed cells to

1

BAYER 18

the normal growth phenotype (see: Daum et al. Trends Biochem. Sci. 1994, 19, 474-80;
Fridman et al. J. Biol. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 426-
28) have further indicated that inhibition of raf expression by antisense RNA blocks cell
proliferation in membrane -associated oncogenes. Similarly, inhibition of raf kinase (by
5 antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition
of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2, 668-
75).

Summary of the Invention

10 The present invention provides compounds which are inhibitors of the enzyme raf kinase.
Since the enzyme is a downstream effector of p21 ras , the inhibitors are useful in
pharmaceutical compositions for human or veterinary use where inhibition of the raf
kinase pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth
mediated by raf kinase. In particular, the compounds are useful in the treatment of

15 human or animal solid cancers, e.g., murine cancer, since the progression of these cancers
is dependent upon the ras protein signal transduction cascade and therefore susceptible to
treatment by interruption of the cascade, i.e., by inhibiting raf kinase. Accordingly, the
compounds of the invention are useful in treating cancers, including solid cancers, such
as, for example, carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon),

20 myeloid disorders (e.g., myeloid leukemia) or adenomas (e.g., villous colon adenoma).

The present invention therefore provides compounds generally described as aryl ureas,
including both aryl and heteroaryl analogues, which inhibit the raf kinase pathway. The
invention also provides a method for treating a raf mediated disease state in humans or
25 mammals. Thus, the invention is directed to compounds which inhibit the enzyme raf
kinase and also compounds, compositions and methods for the treatment of cancerous
cell growth mediated by raf kinase wherein a compound ,of Formula I is administered or
pharmaceutically acceptable salt thereof.

A - D - B (I)

30 In formula I, D is -NH-C(0)-NH-,

BAYER IS

A is a substituted moiety of up to 40 carbon atoms of the formula: -L-CM-L 1 ) q
, where L is a 5 or 6 membered cyclic structure bound directly to D, L 1 comprises a
substituted cyclic moiety having at least 5 members, M is a bridging group having at least
one atom, q is an integer of from 1-3; and each cyclic structure of L and L 1 contains 0-4
5 members of the group consisting of nitrogen, oxygen and sulfur, and

B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of
up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D
containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur,

wherein L 1 is substituted by at least one substituent selected from the group
10 consisting of -S0 2 R x , -C(0)R x and -C(NR y ) R b

R y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally
containing heteroatoms selected from N, S and O and Optionally halosubstituted, up to
per halo,

R z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally
15 - containing heteroatoms selected from N, S and O and optionally substituted by halogen,
hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally
contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

R x is R z or NR a R b where R a and Rb are

a) independently hydrogen,

20 a carbon based moiety of up to 30 carbon atoms optionally containing

heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy
and carbon based substituents of up to 24 carbon atoms, which optionally contain
heteroatoms selected from N, S and O and are optionally substituted by halogen, or

-OSi(Rf)3 where R f is hydrogen or a carbon based moiety of up to 24
25 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally
substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms,
which optionally contain heteroatoms selected from N, S and O and are optionally
substituted by halogen; or

3

BAYER 18

b) R a and R b together form a 5-7 member heterocyclic structure of 1-3
heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic
structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy
or carbon based substituents of up to 24 carbon atoms, which optionally contain

5 heteroatoms selected from N, S and O and are optionally substituted by halogen; or

c) one of Ri or R b is -C(0)-, a Ci-Cs divalent alkylene group or a substituted
C1-C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at
least 5 members, wherein the substituents of the substituted C1-C5 divalent alkylene
group are selected from the group consisting of halogen, hydroxy, and carbon based

10 substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected
from N, S and O and are optionally substituted by halogen;

where B is substituted, L is substituted or L 1 is additionally substituted, the
substituents are selected from the group consisting of halogen, up to per-halo, and Wn,
where n is 0-3 ;

15 wherein each W is independently selected from the group consisting of -CN,

-C0 2 R 7 , -C(0)NR 7 R 7 , -C(0)-R 7 , -N0 2 , -OR 7 , -SR 7 , -NR 7 R 7 , -NR 7 C(0)OR 7 , -
NR 7 C(0)R 7 , -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally
containing heteroatoms selected from N, S and O and optionally substituted by one or
more substituents independentiy selected from the group consisting of -CN, -CO2R 7 , -

20 C(0)R 7 , -C(0)NR 7 R 7 , -OR 7 , -SR 7 , -NR 7 R 7 , -N0 2 , -NR 7 C(0)R 7 , -NR 7 C(0)OR 7 and
halogen up to per-halo; with each R 7 independently selected from H or a carbon based
moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S
and O and opdonally substituted by halogen,

wherein Q is -0-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(0>, -CH(OH)-, -(CH 2 ) m O-, -
25 (CH 2 ) m S-, -(CH 2 ) m N(R 7 )-, -0(CH 2 ) m - CHX\ -CXY, -S-(CH 2 ) m - and -N(R 7 )(CH 2 ) m -,
where m= 1-3, and X a is halogen; and

Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from
the group consisting of nitrogen, oxygen and sulfur, which is opdonally substituted by
halogen, up to per-halo, and optionally substituted by Z n i, wherein nl is 0 to 3 and each Z

4

BAYER 18

MR*

is independently selected from the group consisting of -CN, -COjR 7 , -C(0)R',
-C(0)NR 7 R 7 , -N0 2> -OR 7 , - SR 7 -NR 7 R 7 , -NR 7 C(0)OR 7 , -NR 7 C(0)R 7 , and a carbon
based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from
N, S and 0 and optionally substituted by one or more substituents selected from the
5 group consisting of -CN, -C0 2 R 7 , -COR 7 , -C(0)NR 7 R 7 , -OR 7 , -SR 7 , -N0 2 , -NR 7 R 7 ,
-NR 7 C(0)R 7 , and -NR 7 C(0)OR 7 , with R 7 as defined above.

Li formula I, suitable hetaryl groups include, but are not limited to, 5-12 carbon-
atom aromatic rings or ring systems containing 1-3 rings, at least one of which is
10 aromatic, in which one or more, e.g., 1-4 carbon atoms in one or more of the rings can be
replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For
example, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-,

2- , 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-
isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-

15 pyrimidinyl, 'l,2,3-triazol-l-, -4- or -5-yl, 1,2,4-triazol-l-, -3- or -5-yl, 1- or 5-tetrazolyl,

1.2.3- oxadiazol-4- or -5-yl, l,2,4-oxadiazol-3- or -5-yl, l,3,4-thiadiazol-2- or -5-yl,

1.2.4- oxadiazol-3- or -5-yl, l,3,4-thiadiazol-2- or -5-yl, l,3,4-thiadiazol-3- or -5-yl,
l,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl,

3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-
20 benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-

, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5- 6- or 7-benzisoxazolyl,
1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-
benz-l,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-
isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2-,

25 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally optionally substituted phenyl, 2- or 3-
thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyi, etc. For
example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, l-methyl-3-
pyrryl, l-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-l,2,4-thiadiazol-2-yl.

Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc. throughout

30 include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched
isomers such as isopropyl, isobutyl, sec-butyl, ferr-butyl, etc.

5

BAYER 18

Suitable aryl groups which do not contain heteroatoms include, for example,
phenyl and 1- and 2-naphthyl.

The term "cycloalkyl", as used herein, refers to cyclic structures with or without
alky! substituents such that, for example, "C4 cycloalkyl" includes methyl substituted
5 cyclopropyl groups as well as cyclobutyl groups. The term "cycloalkyl", as used herein
also includes saturated heterocyclic groups.

Suitable halogen groups include F, CI, Br, and/or I, from one to per-substitution
(i.e. all H atoms on a group replaced by a halogen atom) being possible where an alkyl
group is substituted by halogen, mixed substitution of halogen atom types also being
10 possible on a given moiety.

The invention also relates to compounds per se, of formula I.

The present invention is also directed to pharmaceutically acceptable salts of formula I.
Suitable pharmaceutically acceptable salts are well known to those skilled in the art and

15 include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic
acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic
acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-
naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric
acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid,

20 salicylic acid, phenyiacetic acid, and mandelic acid. In addition, pharmaceutically
acceptable salts include acid salts of inorganic bases, such as salts containing alkaline
cations (e.g., Li + Na + or K + ), alkaline earth cations (e.g., Mg 4 " 2 , Ca +2 or Ba +2 ), the
ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic
substituted ammonium, and quaternary ammonium cations, such as those arising from

25 protonation or peralkylation of triethylamine, Af iV-diethylamine, MiV-dicyclohexylamine,
lysine, pyridine, iV,JV-dimethylarmnopyridine (DMAP), l,4-diazabiclo[2.2.2]octane
(DAB CO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and l,8-diazabicyclo[5.4.0]undec-7-
ene (DBU).

30 A number of the compounds of Formula I possess asymmetric carbons and can therefor
exist in racemic and optically active forms. Methods of separation of enantiomeric and

6

BAYER 18

diastereomeric mixtures are well known to one skilled in the art. The present invention
encompasses any isolated racemic or optically active form of compounds described in
Formula I which possess raf inhibitory activity.

The compounds of Formula I may be prepared by the use of known chemical reactions
and procedures, some from starting materials which are commercially available.
Nevertheless, general preparative methods are provided below to aid one skilled in the art
in synthesizing these compounds, with more detailed examples being provided in the
Experimental section which follows.

Substituted anilines may be generated using standard methods (March. Advanced
Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985). Larock. Comprehensive
Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme I,
aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst,
such as Ni, Pd, or Pt, and H2 or a hydride transfer agent, such as formate, cyclohexadiene,
or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK
(1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as
LiAlKj (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic
Synthesis; VCH Publishers: New York (1991)), or using a zero valent metal, such as Fe,
Sn or Ca, often in acidic media. Many methods exist for the synthesis of nitroaryls
(March. Advanced Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985). Larock.
Comprehensive Organic Transformations; VCH Publishers: New York (1989)).

General Preparative Methods

H 2 / catalyst

(eg. Ni, Pd, Pt)

ArN0 2

[H"j

ArNH 2

(eg. Fs, Sn, Ca)

Scheme I

Reduction of Nitroaryls to Aryl Amines

7

BAYER 18

15

Nitroaryls are commonly formed by electrophilic aromatic nitration using HN03, or an
alternative NO2" 1 " source. Nitroaryls may be further elaborated prior to reduction. Thus,
nitroaryls substituted with

HN0 3

Ar-H ArN0 2

potential leaving groups (e.g. F, CI, Br, etc.) may undergo substitution reactions on
treatment with nucleophiles, such as thiolate (exemplified in Scheme U) or phenoxide.
Nitroaryls may also undergo Ullman-type coupling reactions (Scheme II).

0 2 N.
FT

ArSH

base

-, 0 2 N.

C5 \-S-Ar

(> VSH "

0 2 N. J s _ .

* ^T^v Br-Ar

R'

CuO / base

3

Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls

10 Nitroaryls may also undergo transition metal mediated cross coupling reactions. For
example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo
palladium mediated cross coupling reactions with aryl nucleophiles, such as arylboronic
acids (Suzuki reactions, exemplified below), aryltins (Stille reactions) or arylzincs
(Negishi reaction) to afford the biaryl (5).

0 2 N^^ ArB(OR')a °2 N \>r^

^ \\_ x > y_ Ar

R -^=/ Pd(0) r""^=/

4 5

Either nitroaryls or anilines may be convened into the corresponding arenesulfonyl
chloride (7) on treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with
a fluoride source, such as KF then affords sulfonyl fluoride (8). Reaction of sulfonyl

8

BAYER 18

fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, such
as tris(dimethylarmno)sulfonium difluorotrimethylsiliconate (TASF) leads to the
corresponding trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 may be
reduced to the arenethiol (10), for example with zinc amalgum. Reaction of thiol 10 with
CHCIF2 in the presence of base gives the difluoromethyl mercaptam (11), which may be
oxidized to the sulfone (12) with any of a variety of oxidants, including CrCVacetic
anhydride (Sedova et al. Zh. Org. Khim. 1970, 6, (568).

S0 2 CI

Scheme III Selected Methods of Fluorinated Aryl Sulfone Synthesis

As shown in Scheme IV, non-symmetrical urea formation may involve reaction of an aryl
isocyanate (14) with an aryl amine (13). The heteroaryl isocyanate may be synthesized
from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as

9

BAYER 18

trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate
(triphosgene), or A^N'-carbonyldiirnidazoIe (CDI). The isocyanate may also be derived
from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an
anhydride by a Curtius-type rearrangement. Thus, reaction of acid derivative 16 with an
azide source, followed by rearrangement affords the isocyanate. The corresponding
carboxylic acid (17) may also be subjected to Curtius-type rearrangements using
diphenylphosphoryl azide (DPP A) or a similar reagent.

Ar 1 — NH 2 13
COC! 2

. H 2 N— Ar 2
Ar-NCO

14

DPPA

H H
15

Ar" ' X

16 17

Scheme IV Selected Methods of Non-Symmetrical Urea Formation

Finally, ureas may be further manipulated using methods familiar to those skilled in the
art.

The invention also includes pharmaceutical compositions including a compound of
Formula I, and a physiologically acceptable carrier.

The compounds may be administered orally, topically, parenterally, by inhalation or
spray or rectally in dosage unit formulations. The term 'administration by injection'
includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as
use of infusion techniques. One or more compounds may be present in association with
one or more non-toxic pharmaceutically acceptable carriers and if desired other active
ingredients.

10

BAYER 18

Compositions intended for oral use may be prepared according to any suitable method
known to the art for the manufacture of pharmaceutical compositions. Such
compositions may contain one or more agents selected from the group consisting of
diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in
order to provide palatable preparations. Tablets contain the active ingredient in
admixture with non-toxic pharmaceutic ally acceptable excipients which are suitable for
the manufacture of tablets. These excipients may be, for example, inert diluents, such as
calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or alginic acid; and
binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be
uncoated or they may be coated by known techniques to delay disintegration and
adsorption in the gastrointestinal tract and thereby provide a sustained action over a
longer period. - For example, a time delay material such as glyceryl monostearate or
glyceryl distearate may be employed. These compounds may also be prepared in solid,
rapidly released form.

Formulations for oral use may also be presented as hard gelatin capsules wherein the
active ingredient is mixed with an inert solid diluent, for example, calcium carbonate,
calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is
mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable
for the manufacture of aqueous suspensions. Such excipients are suspending agents, for
example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl
methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents may be a naturally occurring phosphatide, for example,
lecithin, or condensation products or an alkylene oxide with fatty acids, for example
polyoxyethylene stearate, or condensation products of ethylene oxide with long chain
aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products
of ethylene oxide with partial esters derived from fatty acids and hexitol such as

ll

BAYER 18

polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with
partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring
5 agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose
or saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by
the addition of water provide the active ingredient in admixture with a dispersing or
10 wetting agent, suspending agent and one or more preservatives. Suitable dispersing or
wetting agents and suspending agents are exemplified by those already mentioned above.
Additional excipients, for example, sweetening, flavoring and coloring agents, may also
be present.

15 The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily
suspensions which may be formulated by suspending the active ingredients in a vegetable
oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as
liquid paraffin. The oily suspensions may contain a thickening agent, for example
beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above,

20 and flavoring agents may be added to provide palatable oral preparations. These
compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water
emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or

25 a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying
agents may be naturally-occurring gums, for example gum acacia or gum tragacanth,
naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial
esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate,
and condensation products of the said partial esters with ethylene oxide, for example

30 polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and
flavoring agents.

12

BAYER 18

Syrups and elixirs may be formulated with sweetening agents, for example glycerol,
propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a
preservative and flavoring and coloring agents.

The compounds may also be administered in the form of suppositories for rectal
administration of the drug. These compositions can be prepared by mixing the drug with
a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the
rectal temperature and will therefore melt in the rectum to release the drug. Such
10 materials include cocoa butter and polyethylene glycols.

y For all regimens of use disclosed herein for compounds of Formula I, the daily oral

? if dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The

' % 4 daily dosage for administration by injection, including intravenous, intramuscular,

U, 15 subcutaneous and parenteral injections, and use of infusion techniques will preferably be

jj= from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regime will

h 4 preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage

J regime will preferably be from 0.1 to 200 mg administered between one to four times
daily. The daily inhalation dosage regime will preferably be from 0.01 to 10 mg/Kg of

20 total body weight.

It will be appreciated by those skilled in the art that the particular method of
administration will depend on a variety of factors, all of which are considered routinely
when administering therapeutics. It will also be appreciated by one skilled in the art that

25 the specific dose level for a given patient depends on a variety of factors, including
specific activity of the compound administered, age, body weight, health, sex, diet, time
and route of administration, rate of excretion, etc. It will be further appreciated by one
skilled in the art that the optimal course of treatment, ie., the mode of treatment and the
daily number of doses of a compound of Formula I or a phaimaceutically acceptable salt

30 thereof given for a defined number of days, can be ascertained by those skilled in the art
using conventional treatment tests.

"13

BAYER 18

It will be understood, however, that the specific dose level for any particular patient will
depend upon a variety of factors, including the activity of the specific compound
employed, the age, body weight, general ■health, sex, diet, time of administration, route of
administration, and rate of excretion, drug combination and the severity of the condition
undergoing therapy.

The entire enclosure of all applications, patents and publications cited above and below
are hereby incorporated by reference, including provisional application Serial No.
60/115,877, filed January . 13, 1999 and non-provisional application Serial No.
09/257,266 filed February 25, 1999.

The compounds can be produced from known compounds (or from starting materials
which, in turn, can be produced from known compounds), e.g., through the general
preparative methods shown below. The activity of a given compound to inhibit raf
kinase can be routinely assayed, e.g., according to procedures disclosed below. The
following examples are for illustrative purposes only and are not intended, nor should
they be construed to limit the invention in any way.

EXAMPLES

All reactions were performed in flame-dried or oven-dried glassware under a positive
pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise
indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and
introduced into reaction vessels through rubber septa. Unless otherwise stated, the term
'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at
approximately 15 mmHg. Unless otherwise stated, the term 'under high vacuum' refers-
to a vacuum of 0.4 - 1.0 mmHg.

All temperatures are reported uncorrected in degrees Celsius (°C). Unless otherwise
indicated; all parts and percentages are by weight.

14

BAYER 18

Commercial grade reagents and solvents were used without further purification. N-
cyclohexyl-iVXniethylpolystyrene)carbodiirnide was purchased from Calbiochem-
Novabiochem Corp. 3-terr-Butylaniline, 5-fert-butyl-2-methoxyaniline, 4-bromo-3-
(trifludromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline 2-methoxy-5-

5 (trifluoromethyl)aniline, 4-ferr-butyl-2-nitroaniline, 3-amino-2-naphthoI, ethyl 4-
isocyanatobenzoate, iV-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-
chloro-3-(trifluoromethyl)phenyl isocyanate were purchased and used without further
purification. Syntheses of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A.
Cordi et al. EP 542,609; IBID Bioorg. Med. Chem.. 3, 1995, 129), 4-(3-
10 carbamoylphenoxy)-l-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem.
Abstr. 53, 1959, 12761b), 3-terf-butylphenyl isocyanate (O. Rohr et al. DE 2,436,108)
and 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (K. Inukai et al. JP 42,025,067;
IBID Kogyo Kagaku Zasshi 70, 1967, 491) have previously been described.

15 Thin-layer chromatography (TLC) was performed using Whatman® pre-coated glass-
backed silica gel 60A F-254 250 um plates. Visualization of plates was effected by one
or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine
vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol
followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by

20 heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-
dmitrophenylhydrazine followed by heating. Column chromatography (flash
chromatography) was performed using 230-400 mesh EM Science® silica gel.

Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or
25 a Mettier FP66 automated melting point apparatus and are uncorrected. Fourier
transform infrared spectra were obtained using a Mattson 4020 Galaxy Series
spectrophotometer. Proton ('H) nuclear magnetic resonance (NMR) spectra were
measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either
Me 4 Si (5 0.00) or residual protonated solvent (CHC1 3 5 7.26; MeOH 5 3.30; DMSO 5
30 2.49) as standard. Carbon ( !j C) NMR spectra were measured with a General Electric
GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1 3 8 77.0; MeOD-d 3 ; 5 49.0;

15

BAYER 18

DMS0-d6 6 39.5) as standard. Low resolution mass spectra (MS) and high resolution
mass spectra (HRMS) were either obtained as electron impact (EI) mass spectra or as fast
atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were
obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics
Desorption Chemical Ionization Probe for sample introduction. The ion source was
maintained at 250 °C. Electron impact ionization was performed with electron energy of
70 eV and a trap current of 300 uA. Liquid-cesium secondary ion mass spectra (FAB-
MS), an updated version, of fast atom bombardment were obtained using a Kratos
Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained
using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent
gas (lxlO" 4 torr to 2.5xl0" 4 torr). The direct insertion desorption chemical ionization
(DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10
amps until all traces of the sample disappeared ( -1-2 min). Spectra were scanned from
50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were
obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a
variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass
spectrometer with electrospray ionization. Spectra were scanned from 120-800 amu
using a variable ion time according to the number of ions in the source. Gas
chromatography - ion selective mass spectra (GC-MS) were obtained with a Hewlett
Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33
' mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass .Selective Detector
(ionization energy 70 eV). Elemental analyses are conducted by Robertson Microlit
Labs, Madison NJ.

All compounds displayed NMR spectra, LRMS and either elemental analysis or HRMS
consistent with assigned structures.

List of Abbreviations and Acronyms:

AcOH acetic acid

anh anhydrous
atm atmosphere(s)

16

BAYER 18

BOC rert-butoxycarbonyl

CDI 1, 1 '-carbon yl diimidazole

cone concentrated

d day(s)

5 dec decomposition

DMAC N,iV-dimethylacetamide

DMPU l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone

DMF N,jV-dimethylformamide

DMSO dimethylsulf oxide

10 DPP A diphenylphosphoryl azide

EDCI l-(3-dimethylarninopropyl)-3-ethylcarbodiimide

EtOAc ethyl acetate

EtOH ethanol (100%)

Et 2 0 diethyl ether

15 Et 3 N triethylamine

h hour(s)

HOBT 1-hydroxybenzotriazole

' m-CPBA 3-chloroperoxybenzoic acid

MeOH methanol

20 pet. ether petroleum ether (boiling range 30-60 °C)

temp. temperature

THF tetrahydrofuran

TFA trifluoroAcOH

Tf trifluoromethanesulfonyl

25

A. General Methods for Synthesis of Substituted Anilines

Al. General Method for Aryl Amine Formation via Ether Formation
Followed by Ester Saponification, Curtius Rearrangement, and
Carbamate Deprotection. Synthesis of 2-Amino-3-

30 methoxynaphthalene.

17

BAYER 18

C0 2 Me
OMe "

Step 1. Methyl 3-methoxy-2-naphthoate

A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K 2 C0 3 (7.96 g, 57.6
mmol) in DMF (200 mL) was stirred at room temp, for 15 min., then treated with
iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp,
overnight, then was treated with water (200 mL). The resulting mixture was extracted
with EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated
NaCl solution (100 mL), dried (MgSCU), concentrated under reduced pressure
(approximately 0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an
amber oil (10.30 g): 'H-NMR (DMSO-de) 5 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, .7=8.09
Hz, 1H), 7.44 (s, 1H), 7.53 (app t, 7=8.09 Hz, 1H), 7.84 (d, 7=8.09 Hz, 1H) ; 7.90 (s, 1H),
8.21 (s, 1H).

OMe

Step 2. 3-Methoxy-2-naphthoic acid

A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in
MeOH (100 mL) at room temp, was treated with a 1 N NaOH solution (33.4 mL, 33.4
mmol). The mixture was heated at the reflux temp, for 3 h, cooled to room temp., and
made acidic with a 10% citric acid solution. The resulting solution was extracted with
EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCl
solution, dried (MgS0 4 ) and concentrated under reduced pressure. The residue was
triturated with hexane then washed several times with hexane to give 3-methoxy-2-
naphthoic acid as a white solid (5.40 g, 92%): X H-NMR (DMSO-d*) 5 3.88 (s, 3H), 7.34-
7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, 7=8.09 Hz, 1H), 7.91 (d, 7=8.09 Hz, 1H), 8.19
(s, 1H), 12.83 (br s, 1H).

18

BAYER 18

Step 3. 2-(iV-(CarbobenzyIoxy)amino-3-methoxynaphthalene

A solution of 3-methoxy-2 -naphthoic acid (3.36 g, 16.6 mmol) and Et 3 N (2.59 mL, 18.6
mmol) in anh toluene (70 mL) was stirred at room temp, for 15 min., then treated with a
solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting
mixture was heated at 80 °C for 2 h. After cooling the mixture to room temp., benzyl
alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then warmed to 80
°C overnight. The resulting mixture was cooled to room temp., quenched with a 10%
citric acid solution, and extracted with EtOAc (2 x 100 mL). The combined organic
layers were washed with a saturated NaCl solution, dried (MgS0 4 ) and concentrated
under reduced pressure. The residue was purified by column chromatography (14%
EtOAc/86% hexane) to give 2-(iV-(carbobenzyloxy)amino-3-methoxynaphthalene as a
pale yellow oil (5.1 g, 100%): 'H-NMR (DMSO-d 6 ) 5 3.89 (s, 3H), 5.17 (s, 2H), 7.27-
7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H).

OMe

Step 4. 2-Amino-3-methoxynaphthalene

A slurry of 2-(A^-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and
10% Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a H2 atm (balloon) at room
temp, overnight. The resulting mixture was filtered through Celite® and concentrated
under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder
(2.40 g, 85%): 1_ H-NMR (DMSO-ds) 8 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43
(d, 7=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H); EI-MS m/z 173 (M*)-

A2. Synthesis of a>Carbamyl Anilines via Formation of a

Carbamylpyridine Followed by Nucleophilic Coupling with an Aryl

19

BAYER 18

Amine. Synthesis of 4-(2-A^Methykarbamyl-4-pyridyloxy)aniline

0

CI

NHMe

Step la.

Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide via the

Menisci reaction

Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution
of 4-chloropyridine (10.0 g) in A^-methylformamide (250 mL) at room temp, was added
cone. H 2 S0 4 (3.55 mL) to generate an exotherm. To this mixture was added H 2 0 2 (30%
wt in H 2 0, 17 mL) followed by FeS0 4 '7H 2 0 (0.56 g) to generate another exotherm. The
resulting mixture was stirred in the dark at room temp, for 1 h, then warmed slowly over
4 h to 45 °C. When bubbling had subsided, the reaction was heated at 60 °C for 16 h.
The resulting opaque brown solution was diluted with H 2 0 (700 mL) followed by a 10%
NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500
mL). The organic phases were washed separately with a saturated NaCl solution (3 x 150
mL), then they were combined, dried (MgS0 4 ) and filtered through a pad of silica gel
with the aid of EtOAc. The resulting brown oil was purified by column chromatography
(gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting
yellow oil crystallized at 0 °C over 72 h' to give 4-chlorowV-methyl-2-
pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) R/0.50; [ H NMR
(CDCI3) 5 3.04 (d, 7=5.1 Hz, 3H), 7.43 (dd, 7=5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 (s,
1H), 8.44 (d, 7=5.1 Hz, 1 H); CI-MS m/z 171 ((M+H) + ).

Anhydrous DMF (6.0 mL) was slowly added to SOCl 2 (180'mL) between 40° and 50 °C.
The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g,
487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 °C

O

Step lb.

Synthesis of 4-chloropyridine-2-carbonyl chloride HC1 salt via
picolinic acid

20

BAYER 18

(vigorous S0 2 evolution) for 16 h to generate a yellow solid precipitate. The resulting
mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to
200 mL. The toluene addition/concentration process was repeated twice. The resulting
nearly dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and
5 dried under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HC1 salt
as a yellow-orange solid (92.0 g, 89%).

Step 2. . Synthesis of methyl 4-chloropyridine-2-carboxylate HC1 salt

Anh DMF (10.0 mL) was slowly added to SOCl 2 (300 mL) at 40-48 °C. The solution
10 was stirred at that temp, range for 10 min., then picolinic acid (100 g, 812 mmol) was
added over 30 min. The resulting solution was heated at 72 °C (vigorous S0 2 evolution)
for 16 h to generate a yellow solid. The resulting mixture was cooled to room temp.,
diluted with toluene (500 mL) and concentrated to 200 mL. The toluene
addition/concentration process was repeated twice. The resulting nearly dry residue was
15 filtered, and the solids were washed with toluene (50 mL) and dried under high vacuum
for 4 hours to afford 4-chloropyridine-2-carbonyl chloride HC1 salt as an off-white solid
(27.2 g, 16%). This material was set aside.

The red filtrate was added to MeOH (200 mL) at a rate which kept the internal
20 temperature below 55 °C. The contents were stirred at room temp, for 45 min., cooled to
5 °C and treated with Et 2 0 (200 mL) dropwise. The resulting solids were filtered,
washed with Et 2 0 (200 mL) and dried under reduced pressure at 35 °C to provide methyl
4-chloropyridine-2-carboxylate HC1 salt as a white solid (110 g, 65%): mp 108-112 °C;
'H-NMR (DMSO-d 6 ) 5 3.88 (s, 3H); 7.82 (dd, 7=5.5, 2.2 Hz, 1H); 8.08 (d, 7=2.2 Hz,
25 1H); 8.68 (d, 7=5.5 Hz, 1H); 10.68 (br s, 1H); HPLC ES-MS m/z 172 ((M+H) + ).

O

NHMe

21

BAYER 18

Step 3a. Synthesis of 4-chloro-iV-methyl-2-pyridinecarboxamide from methyl
4-chloropyridine-2-carboxyIate

A suspension of methy] 4-chloropyridine-2-carboxylate HC1 salt (89.0 g, 428 mmol) in
MeOH (75 mL) at 0 °C was treated with a 2.0 M methylamine solution in THF (1 L) at a
5 rate which kept the internal temp, below 5 °C. The resulting mixture was stored at 3 °C
for 5 h, then concentrated under reduced pressure. The resulting solids were suspended
in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500
mL), dried (Na 2 S04.) and concentrated under reduced pressure to afford 4-chloro-/V-
methyI-2-pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43 °C; 1 H-
10 NMR (DMSO-ds) 5 2.81 (s, 3H), 7.74 (dd, 7=5.1, 2.2 Hz, 1H), 8.00 (d, 7=2.2, 1H), 8.61
(d, 7=5.1 Hz, 1H), 8.85 (brd, 1H); CI-MS m/z 171 ((M+H) + ).

O

Step 3b. Synthesis of 4-chloro-JV-methyl-2-pyridinecarboxamide from 4-
chloropyridine-2-carbonyl chloride

15 4-Chloropyridine-2-carbonyl chloride HC1 salt (7.0 g, 32.95 mmol) was added in portions
to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0
°C. The resulting mixture was stored at 3 °C for 4 h, then concentrated under reduced
pressure. The resulting nearly dry solids were suspended in EtOAc (100 mL) and
filtered. The filtrate was washed with a saturated NaCl solution (2 x 100 mL), dried

20 (Na 2 S04) and concentrated under reduced pressure to provide 4-chloro-A r -methyl-2-
pyridinecarboxamide as a yellow, crystalline solid (4.95 g, 88%): mp 37-40 °C.

O

Step 4. Synthesis of 4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated
25 with potassium rm-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was
stirred at room temp, for 2 h. The contents were treated with 4-chloro-iV-methyl-2-
pyridinecarboxamide (15.0 g, 87.9 mmol) and K2CO3 (6.50 g, 47.0 mmol) and then

'NHMe

22

BAYER IS

heated at 80 °C for 8 h. The mixture was cooled to room temp, and separated between
EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was 'back-
extracted with EtOAc (300 mL). The combined organic layers were washed with a
saturated NaCl solution (4 x 1000 mL), dried (Na 2 S0 4 ) and concentrated under reduced
5 pressure. The resulting solids were dried under reduced pressure at 35 °C for 3 h to
afford 4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)aniline as a light-brown solid 17.9 g,
84%): ! H-NMR (DMSO-d 6 ) 5 2.77 (d, 7=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86
(AA'BB' quartet, 7=8.4 Hz, 4H), 7.06 (dd, 7=5.5, 2.5 Hz, 1H), 7.33 (d, 7=2.5 Hz, 1H),
8.44 (d, 7=5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 ((M+H) + ).
10 A3. General Method for the Synthesis of Anilines by Nucleophilic

Aromatic Addition Followed by Nitroarene Reduction. Synthesis of 5-

(4-Aminophenoxy)isoindoline-l,3-dione

O

15 Step 1. Synthesis of 5-hydroxyisoindoline-l,3-dione

To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in cone. AcOH (25 mL) was
slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was
heated at 120 °C for 45 min., then the clear, bright yellow mixture was heated at 160 °C
for 2 h. The resulting mixture was maintained at 160 °C and was concentrated to
20 approximately 15 mL, then was cooled to room temp, and adjusted pH 10 with a IN
NaOH solution. This mixture was cooled to 0 °C and slowly acidified to pH 5 using a IN
HC1 solution. The resultant precipitate was collected by filtration and dried under
reduced pressure to yield 5-hydroxyisoindoline-l,3-dione as a pale yellow powder as
product (3.24 g, 72%): l K NMR (DMSO-d*) 5 7.00-7.03 (m, 2H), 7.56 (d, 7=9.3Hz, 1H).

25

0 2 N

23

BAYER 18

Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-l,3-dione

To a stirring slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 °C was added a
solution of 5-hydroxyisoindoline-l,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL)
dropwise. The bright yellow-green mixture was allowed to return to room temp, and was

5 stirred for 1 h, then l-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in
3-4 portions. The resulting mixture was heated at 70 °C overnight, then cooled to room
temp, and diluted slowly with water (150 mL), and extracted with EtOAc (2 x 100 mL).
The combined organic layers were dried (MgS0 4 ) and concentrated under reduced
pressure to give 5-(4-rutrophenoxy)isoindoline-l,3-dione as a yellow solid (3.3 g, 62%):

10 TLC (30% EtOAc/70% hexane) R/0.28; 1H NMR (DMSO-de) 5 7.32 (d, 7=12 Hz, 2H),
7.52-7.57 (m, 2H), 7.89(d, 7=7.8 Hz, 1H), 8.29 (d, 7=9 Hz, 2H), 11.43 (br s, 1H); CI-MS
m/z 285 ((M+H) + , 100%).

Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-l,3-dione

15 A solution of 5-(4-nitrophenoxy)isoindoline-l,3-dione (0.6 g, 2.11 mmol) in cone. AcOH
(12 mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g,
55.9 mmol) was added slowly. This mixture stirred at room temp, for 72 h, then was
diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined
• organic layers were dried (MgS0 4 ) and concentrated under reduced pressure to give 5-(4-

20 aminophenoxy)isoindoline-l,3-dione as a brownish solid (0.4 g, 75%): TLC (50%
EtOAc/50% hexane) R/0.27; l U NMR (DMSO-dg) 8 5.14 (br s, 2H), 6.62 (d, 7=8.7 Hz,
2H), 6.84 (d, 7=8.7 Hz, 2H), 7.03 (d, 7=2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, 7=8.4 Hz,
1H), 1 1.02 (s, 1H); HPLC ES-MS m/z 255 ((M+H) + , 100%).

25 A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-

tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline

24

BAYER 18

Step 1. Synthesis of l-(4-te^butyl-2-nitrophenyl)-2,5-dimethylpyrrole

To a stirring solution of 2-nitro-4-terf-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10
mL) was added AcOH (O.lmL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe.

5 The reaction mixture was heated at 120 °C for 72 h with azeotropic removal of volatiles.
The reaction mixture was cooled to room temp., diluted with CH2CI2 (10 mL) and
sequentially washed with a IN HC1 solution (15 mL), a IN NaOH solution (15 mL) and a
• saturated NaCl solution (15mL), dried ( MgS0 4 ) and concentrated under reduced
pressure. The resulting orange-brown solids were purified via column chromatography

10 (60 g Si0 2 ; gradient from 6% EtOAc/94% hexane to 25% EtOAc/75% hexane) to give 1-
(4-re?t-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%):
TLC (15% EtOAc/85% hexane) R/0.67; l H NMR (CDC1 3 ) d 1.34 (s, 9H), 1.89 (s, 6H),
5.84 (s, 2H), 7.19-7.24 (m, 1H), 7.62 (dd, 1H), 7.88 (d, 7=2.4 Hz, 1H); CI-MS mJz 273
((M+H) + , 50%).

A.

15

Step 2. Synthesis of 5-terf--Butyl-2-(2,5-dimethylpyrrolyl)anilin.e

A slurry of l-(4-^rt-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol),
10%Pd/C (0.056 g) and EtOAc (50 mL) under an H 2 atmosphere (balloon) was stirred for
72 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced
20 pressure to give 5-tert— butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g,
99%): TLC (10% EtOAc/90% hexane) R/0.43; X B. NMR (CDC1 3 ) 5 1.28 (s, 9H), 1.87-
1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, 1H).

'25

BAYER 18

A5.

General Method for the Synthesis of Anilines from Anilines by
Nucleophilic Aromatic Substitution. Synthesis of 4-(2-(N-
Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCl Salt

O

NHMe

H 2 N

HCl

Me

5 A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide
(75 mL) was treated with potassium rm-butoxide (10.86 g, 96.77 mmol) and the black
mixture was stirred at room temp, until the flask had reached room temp. The contents
were then treated with 4-chloro-iV-methyl-2-pyridinecarboxamide (Method A2, Step 3b;

10 and diluted with water (75 mL). The organic layer was extracted with EtOAc (5 x 100
mL). The combined organic layers were washed with a saturated NaCl solution (200
mL), dried (MgS0 4 ) and concentrated under reduced pressure. The residual black oil
was treated with Et 2 0 (50 mL) and sonicated. The solution was then treated with HCl (1
M in Et 2 0; 100 mL) and stirred at room temp, for 5 min. The resulting dark pink solid

15 (7.04 g, 24.1 mmol) was removed by filtration from solution and stored under anaerobic
- conditions at 0 °C prior to use: T H NMR (DMSO-da) 5 2.41 (s, 3H), 2.78 (d, 7=4.4 Hz,
3H), 4.93 (br s, 2H), 7.19 (dd, 7=8.5, 2.6 Hz, 1H), 7.23 (dd, 7=5.5, 2.6 Hz, 1H), 7.26 (d,

7=2.6 Hz, 1H), 7.55 (d, 7=2.6 Hz, 1H), 7.64 (d, 7=8.8 Hz, 1H), 8.55 (d, 7=5.9 Hz, 1H),
8.99 (q, 7=4.8 Hz, 1H).

7.52 g, 44.2 mmol) and heated at 110 °C for 8 h. The mixture was cooled to room temp.

20

A6.

General Method for the Synthesis of Anilines from Hydroxyanilines
by N-Protection, Nucleophilic Aromatric Substitution and
Deprotection. Synthesis of 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)-

2-chloroaniline

25

Step 1:

Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino)phenol

26

BAYER 18

Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was added
2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This
gray slurry was stirred at room temp, for 6 d. The iron was filtered from solution and the
remaining material was concentrated under reduced pressure. The resulting gray solid
was dissolved in water (20 mL). To the resulting yellow solution was added a saturated
NaHCC>3 solution (50 mL). The solid which precipitated from solution was removed.
The filtrate was slowly quenched with the sodium bicarbonate solution until the product
visibly separated from solution (determined was using a mini work-up vial). The slightly
cloudy yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic
layers were washed with a saturated NaCl solution (125 mL), dried (MgSCU) and
concentrated under reduced pressure. The J H NMR (DIVISOR) indicated a 1:1 ratio of
the nitrophenol starting material and the intended product 3-chloro-4-(2,2,2-
trifluoroacetylamino)phenol. The crude material was taken on to the next step without
further purification.

O

H CI

Step 2: Synthesis of 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl

(222-trifluoro)acetamide

A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol)
in dry dimethylacetamide (50 mL) was treated with potassium ferr-butoxide (5.16 g,
45.98 mmol) and the brownish black mixture was stirred at room temp, until the flask had
cooled to room temp. The resulting mixture was' treated with 4-chloro-iV-methyl-2-
pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 °C
under argon for 4 d. The black reaction mixture was cooled to room temp, and then
poured into cold water (100 mL). The mixture was extracted with EtOAc (3 x 75 mL)
and the combined organic layers were concentrated under reduced pressure. The residual
brown oil was purified by column chromatography (gradient from 20% EtOAc/pet. ether
to 40% EtOAc/pet. ether) to yield 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)-2-
chlorophenyl (222-trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).

27

BAYER 18

o

NHMe

Step 3. Synthesis of 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline

A solution of crude 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-
trifluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a IN

5 NaOH solution (20 mL). This brown solution was allowed to stir for 8 h. To this
solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc
(3 x 40 mL) and the solvent was concentrated to yield 4-(2-(A r -Methylcarbamoyl)-4-
pyridyloxy)-2-chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30
mmol): l H NMR (DMSO-de) 5 2.77 (d, 7=4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, 7=8.5, 2.6

10 Hz, 1H), 6.76 (d, 7=2.6 Hz, 1H), 7.03 (d, 7=8.5 Hz, 1H), 7.07 (dd, 7=5.5, 2.6, Hz, 1H),
7.27 (d, 7=2.6 Hz, 1H), 8.46 (d, 7=5.5 Hz, 1H), 8.75 (q, 7=4.8, 1H).

A7. General Method for the Deprotection of an Acylated Aniline.

Synthesis of 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline

OMe

A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g, 14.95
mmol) in a 6M HC1 solution (24 mL) was heated at the reflux temp, for 1 h. The
resulting solution was allowed to cool to room temp, during which time it
solidified slighdy. The resulting mixture was diluted with water (20 mL) then

20 treated with a combination of solid NaOH and a saturated NaHC0 3 solution until

the solution was basic. The organic layer was extracted with CH 2 C1 2 (3 x 50 mL).
The combined organics were dried (MgS0 4 ) and concentrated under reduced
pressure to yield 4-chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil
(3.20 g, 14.2 mmol): l H NMR (DMSO-d 6 ) 5 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s,

25 2H).

28

BAYER 18

A8. General Method for Synthesis of co-Alkoxy-co-carboxyphenyl Anilines.

Synthesis of 4-(3-(A r -Methylcarbamoiy)-4-methoxyphenoxy)aniline.

O

Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene:

5 To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-l-nitrobenzene (prepared from 2,5-
dihydroxybenzoic acid in a manner analogous to that described in Method A13, Step 1,
12 mmol) in acetone (50 mL) was added K2CO3 (5 g) and dimethyl sulfate (3.5 mL). The
resulting mixture was heated at the reflux temp, overnight, then cooled to room temp, and
filtered through a pad of Celite®. The resulting solution was concentrated under reduced
10 pressure, absorbed onto S1O2, and purified by column chromatography (50% EtOAc /
50% hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene as a
yellow powder (3 g): mp 115-118 °C.

O

O a N' "* > " ^^OMe
Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-l-nitrobenzene:

15 A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l -nitrobenzene (1.2 g), KOH
(0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp, overnight and
then heated at the reflux temp, for 4 h. The resulting mixture was cooled to room temp,
and concentrated under reduced pressure. The residue was dissolved in water (50 mL),
and the aqueous mixture was made acidic with a IN HC1 solution. The resulting mixture

20 was extracted with EtOAc (50 mL). The organic layer was dried (MgSCU) and
concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-l-
nitrobenzene (1.04 g).

O

' 0> V^ S [ NHMe

Step 3. 4-(3-(A r -Methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene:

29

BAYER 18

To a solution of 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (0.50 g, 1.75 mmol) in
CH 2 C1 2 (12 mL) was added S0C1 2 (0.64 mL, 8.77 mmol) in portions. The resulting
solution was heated at the reflux temp, for 18 h, cooled to room temp., and concentrated
under reduced pressure. The resulting yellow solids were dissolved in CH2CI2 (3 mL)

5 then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5
mL, 7.02 mmol) in portions (CAUTION: gas evolution), and stirred at room temp, for 4
h. The resulting mixture was treated with a IN NaOH solution, then extracted with
CH2CI2 (25 mL). The organic layer was dried (Na 2 S0 4 ) and concentrated under reduced
pressure to give 4-(3-(A r -methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene as a

10 yellow solid (0.50 g, 95%).

O

- HaN kA 0M

OMe

Step 4. 4-(3-(/V-MethylcarbamoIy)-4-methoxyphenoxy)aniline:

A slurry of 4-(3-(iV-methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene (0.78 g, 2.60
mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under 1 atm of H 2 (balloon)
15 for 2.5 d, then was filtered through a pad of Celite®. The resulting solution was
concentrated under reduced pressure to afford 4-(3-(iV-methylcarbamoIy)-4-
methoxyphenoxy)aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et 3 N/99.9%
EtOAc)R/0.36.

20 A9. General Method for Preparation of co-Alkylphthalimide-containing

Anilines. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-
dione

O

o

Step 1. Synthesis of 5-(4-Nitrophenoxy)-2-methylisoindoline-l,3-dione:

25 A slurry of 5-(4-nitrophenoxy)isoindoline-l,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and
NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp, for 1 h, then treated
with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room

30

BAYER IS

temp, overnight, then was cooled to °C and treated with water (10 mL). The resulting
solids were collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-
methylisoindoline-l,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35%
EtO Ac/65% hexane) R/0.61.

O

O

31

BAYER 18

Step 2. Synthesis of 5-(4-Aminophenoxy)-2-rnethylisoindoline-l,3-dione:

A slurry of mtrophenoxy)-2-methylisoindoline-l,3-dione (0.87 g, 2.78 mmol) and 10%
Pd/C (0.10 g) in MeOH was stirred under 1 atm of-H 2 (balloon) overnight. The resulting
mixture was filtered through a pad of Celite® and concentrated under reduced pressure.
5 The resulting yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug
of Si0 2 (60% EtOAc/40% hexane) to afford 5-(4-aminophenoxy)-2-methylisoindoline-
1,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) R/0.27.

A10. General Method for Synthesis of u>Carbamoylaryl Anilines Through

10 Reaction of co-Alkoxycarbonylaryl Precursors with Amines. Synthesis

of 4-(2-(A'-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline

O

CI

N ^ °

Step 1. Synthesis of 4-Chloro-2-(iV-(2-morpholin-4-

15 ylethyl)carbamoyl)pyridine

To a solution of methyl 4-chloropyridine-2-carboxylate HC1 salt (Method A2, Step 2;
1.01 g, 4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL,
19.4 mmol) dropwise and the resulting solution was heated at the reflux temp, for 20 h,
cooled to room temp., and treated with water (50 -mL). The resulting mixture was
20 extracted with EtOAc (50 mL). The organic layer was dried (MgS0 4 ) and concentrated
under reduced pressure to afford 4-chloro-2-(?/-(2-morpholin-4-
ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH/90%
EtOAc) R f 0.50.

O

H 2 N

32

BAYER 18

fff

Step 2. Synthesis of 4-(2-(A r -(2-Morpholin-4-

ylethyl)carbarnoyI)pyridyloxy)aniIine.

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium f<?rf-butoxide (0.53 g,
4.75 mol) in DMF (8 mL) was stirred at room temp, for 2 h, then was sequentially treated

5 with 4-chloro-2-(A^-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and
K2CO3 (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 °C overnight, cooled
to room temp., and separated between EtOAc (25 mL) and a saturated NaCl solution (25
mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined
organic layers were washed with a saturated NaCl solution (3 x 25 mL) and concentrated

10 under reduced pressure. The resulting brown solids were purified by column
chromatography (58 g; gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to afford
4-(2-(A r <2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10%
MeOH/90% EtOAc) R/0.32.

15 All. General Method for the Reduction of Nitroarenes to Arylamines.

Synthesis of 4-(3-Carboxyphenoxy)aniline.

A slurry of 4-(3-carboxyphenoxy)-l-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd/C
(0.50 g) in MeOH (120 mL) was stirred under an H2 atmosphere (balloon) for 2 d. The
20 resulting mixture was filtered through a pad of Celite®, then concentrated under reduced
pressure to afford 4-(3-carboxyphenoxy)aniline as a brown solid- (2.26 g, 48%): TLC
(10% MeOH/90% CH 2 C1 2 ) R f 0.44 (streaking).

A12. General Method for the Synthesis of Isoindolinone-Containing Anilines.
25 Synthesis of 4-(l-Oxoisoindolin-5-yloxy)aniline.

HCk

NH

O

33

BAYER 18

NH

Step 1. Synthesis of 5-hydroxyisoindolin-l-one

To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was
slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the
reflux temp, for 40 min., filtered hot, and concentrated under reduced pressure. The
5 reaction was repeated on the same scale and the combined oily residue was purified by
column chromatography (1.1 Kg Si0 2 ; gradient from 60% EtOAc/40% hexane to 25%
MeOH/75% EtOAc) to give 5-hydroxyisoindolin-l-one (3.77 g): TLC (100% EtOAc) R/
0.17; HPLC ES-MS m/z 150 ((M+H) + ).

O

10 Step 2. Synthesis of 4-(l-isoindolinon-5-yloxy)-l-nitrobenzene

To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 °C was added 5-hydroxyisoindolin-
l-one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room
temp, and was stirred for 45 min., then 4-fluoro-l -nitrobenzene was added and then
mixture was heated at 70 °C for 3 h. The mixture was cooled to 0 °C and treated with
15 water dropwise until a precipitate formed. The resulting solids were collected to give 4-
(l-isoindolinon-5-yloxy)-l-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC
(100% EtOAc) R/0.35.

H 2 N

O

Step 3. Synthesis of 4-(l-oxoisoindolin-5-yloxy)aniline

20 A slurry of 4-(l-isoindolinon-5-yloxy)-l-nitrobenzene (2.12 g, 7.8 mmol) and 10% PdVC
(0.20 g) in EtOH (50 mL) was stirred under an H 2 atmosphere (balloon) for 4 h, then
filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to
afford 4-(l-oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc) R/
0.15.

25

34

BAYER 18

C3 ' 15

A13. General Method for the Synthesis of co- Carbamoyl Anilines via EDCI-

Mediated Amide Formation Followed by Nitroarene Reduction.
Synthesis of 4-(3-A r -MethylcarbamoyIphenoxy)aniline.

,0,

I J

OM

Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene

A mixture of 4-fiuoro-l -nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g,
150 mmol) and K 2 C0 3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux
.temp, overnight, cooled to room temp, and treated with water (250 mL). The resulting
10 mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were
sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100
mL), dried (Na2SO<0 and concentrated under reduced pressure. The residue was purified
by column chromatography (10% EtO Ac/90% hexane) to afford 4-(3-
ethoxycarbonylphenoxy)-l-nitrobenzene as an oil (38 g).

o

OH

Step 2. Synthesis of 4-(3-carboxyphenoxy)-l-nitrobenzene

To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene (5.14 g,
20 17.9 mmol) in a 3:1 THF/water solution (75 mL) was added a solution LiOH«H 2 0 (1.50
g, 35.8- mmol) in water (36 mL). The resulting mixture was heated at 50 °C overnight,
then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2
with a 1M HC1 solution. The resulting bright yellow solids were removed by filtration
and washed with hexane to give 4-(3-carboxyphenoxy)-l-nitrobenzene (4.40 g, 95%).

O

25

0,N

35

BAYER 18

Step 3. Synthesis of 4-(3-(iY-methylcarbamoyl)phenoxy)-l-nitrobenzene

A mixture of 4-(3-carboxyphenoxy)-l-nitrobenzene (3.72 g, 14.4 mmol), EDCI-HC1
(3.63 g, 18.6 mmol), Af-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M
in THF; 8 mL, 16 mmol) in CH 2 C1 2 (45 mL) was stirred at room temp, for 3 d, then
5 concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and
the resulting mixture was extracted with a 1M HC1 solution (50 mL). The aqueous layer
was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed
with a 'saturated NaCl solution (50 mL), dried (Na 2 S0 4 ), and concentrated under reduced
pressure to give 4-(3-(N-methylcarbamoyl)phenoxy)-l-nitrobenzene as an oil (1.89 g).

O

10

NHMe

Step 4. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)aniline

A slurry of 4-(3-(A r -methylcarbamoyl)phenoxy)-l-nitrobenzene (1.89 g, 6.95 mmol) and
5% Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an H 2 atm (balloon) overnight.
15 The resulting mixture was filtered through a pad of Celite® and concentrated under
reduced pressure. The residue was purified by column chromatography (5% MeOH/95%
CH 2 C1 2 ). The resulting oil solidified under vacuum overnight to give 4-(3-(2V-
methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).

20 A14. General Method for the Synthesis of ci>Carbamoyl Anilines via EDCI-

Mediated Amide Formation Followed by Nitroarene Reduction.
Synthesis of 4-3-(5-Methylcarbamoyl)pyridyloxy)aniline

O

25 Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-l-nitrobenzene

To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl
5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was

36

BAYER 18

added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and
the resulting mixture was heated at 70 °C overnight, cooled to room temp., and treated
with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted
with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The
5 residue was purified by column chromatography (30% EtOAc/70% hexane) to afford 4-
(3-(5-methoxycarbonyl)pyridyloxy)-l-nitrobenzene (0.60 g).

O

Step 2. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline

A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-l -nitrobenzene (0.60 g, 2.20 mmol)
10 and 10% Pd/C in MeOH/EtOAc was stirred under an H2 atmosphere (balloon) for 72 h.
The resulting mixture was filtered and the filtrate was concentrated under reduced
pressure. The residue was purified -by column chromatography (gradient from 10%
EtO Ac/90% hexane to 30% EtO Ac/70% hexane to 50% EtO Ac/50% hexane) to afford 4-
(3-(5-methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): l H NMR (CDCI3) 8 3.92 (s,
15 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 (d, 1H).

37

BAYER 18

A15. Synthesis of an Aniline via Electrophilic Nitration Followed by Reduction.
Synthesis of 4-(3-Methylsulfamoylphenoxy)aniIine.

Step 1. Synthesis of N-methyl-3-bromobenzenesulfonamide

5 To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at
0 °C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution
was allowed to warm to room temp, and was stirred at room temp, overnight. The
resulting mixture was separated between EtOAc (25 mL) and a 1 M HC1 solution (25
mL). The aqueous phase was back-extracted with EtOAc (2 x 25 mL). The combined

10 organic phases were sequentially washed with water (2 x 25 mL) and a saturated NaCl
solution (25 mL), dried (MgSCU) and concentrated under reduced pressure to give N-
methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%).

O, ,,0

Step 2. Synthesis of 4-(3-(iV-methylsuIfamoyl)phenyloxy)benzene

15 To a slurry of phenol (1.9 g, 20 mmol), K 2 C0 3 (6.0 g, 40 mmol), and Cul (4 g, 20 mmol)
in DMF (25 mL) was added A^-methyl-S-bromobenzenesulfonamide (2.5 g, lOmmol), and
the resulting mixture was stirred at the reflux temp, overnight, cooled to room temp., and
separated between EtOAc (50 mL) and a 1 N HC1 solution (50 rhL). The aqueous layer
was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were

20 sequentially washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried
(MgS0 4 ), and concentrated under reduced pressure. The residual oil was purified by
column chromatography (30% EtOAc/70% hexane) to give 4-(3-(iV-
methylsulfamoyl)phenyloxy)benzene (0.30 g).

38

BAYER 18

Step 3. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)-l-nitrobenzene

To a solution of 4-(3-(iV-memylsulfamoyl)phenyIoxy)benzene (0.30 g, 1.14 mmol) in
TFA (6 mL) at -10°C was added NaN0 2 (0.097 g, 1.14 mmol) in portions over 5 min.
The resulting solution was stirred at -10 °C for 1 h, then was allowed to warm to room
temp., and was concentrated under reduced pressure. The residue was separated between
EtOAc (10 mL) and water (10 mL). The organic phase was sequentially washed with
water (10 mL) and a saturated NaCl solution (10 mL), dried (MgSO*) and concentrated
under reduced pressure to give 4-(3-(iV-methylsulfamoyl)phenyloxy)-l -nitrobenzene
(0.20 g). This material carried on to the next step without further purification.

r ,| NHMe
H 2 N' — ^
Step 4. Synthesis of 4-(3-(iV-methylsulfamoyl)phenyloxy)aniline

A slurry of 4-(3-(A r -methylsulfamoyl)phenyloxy)-l -nitrobenzene (0.30 g) and 10% Pd/C
(0.030 g) in EtOAc (20 mL) was stirred under an H 2 atmosphere (balloon) overnight.
The resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated
under reduced pressure. The residue was purified by column chromatography (30%
EtOAc/70% hexane) to give 4-(3-(iV-methylsulfamoyl)phenyloxy)aniline (0.070 g).

A16. Modification of o-ketones. Synthesis of 4-(4-(l-(iV-

methoxy)iminoethyl)phenoxyaniline HQ salt.

HCI ^

H 2 N.

O

To a slurry of 4-(4-acetylphenoxy)aniline HC1 salt (prepared in a manner analogous to
Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0
mL) was added C-methylhydroxylamine HC1 salt (0.65 g, 7.78 mmol, 2.0 equiv.). The
resulting solution was heated at the reflux temperature for 30 min, cooled to room
temperature and concentrated under reduced pressure. The resulting solids were
triturated with water (10 mL) and washed with water to "give 4-(4-(l-(iV-
methoxy)iminoethyl) phenoxyaniline HC1 salt as a yellow solid (0.85 g): TLC (50%

39

BAYER 18

EtO Ac/50% pet. ether) R/0.78; T H NMR (DMSO-ds) 5 3.90 (s, 3H), 5.70 (s, 3H); HPLC-
MS mfz 257 ((M+H) + ).

A17. Synthesis of A4co-Silyloxyalkyl)amides. Synthesis of 4-(4-(2-(A r -(2- '

5 TriisopropylsiIyloxy)ethyIcarbamoyl)pyridyloxyaniline.

Step 1. 4-Chloro-/V-(2-triisopropyIsiIyloxy)ethylpyridine-2-carboxamide

To a solution of 4-chloro-A r -(2-hydroxyethyl)pyridine-2-carboxamide (prepared in a
manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was

10 added triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4
mmol, 2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp, then
was concentrated under reduced pressure. The residue was separated between water (10
mL) and EtOAc (10 mL). The aqueous layer was extracted with EtO Ac (3 x 10 mL).
The combined organic phases were dried (MgSO*), and concentrated under reduced

15 pressure to afford 4-chloro-2-(7y-(2-triisopropylsilyloxy)ethyl)pyridinecarboxarnide as an
orange oil (2.32 g, 88%). This material was used in the next step without further
purification.

Step 2. 4-(4-(2-(Ar-(2-TriisopropyIsiIyIoxy)ethylcarbamoyl)pyridyloxyaniline

20 To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was added -
potassium fert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion causing an
exotherm. When this mixture had cooled to room temperature, a solution of 4-chloro-2-
(W-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) in DMF
(4 mL) was added followed by K 2 C0 3 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting

25 mixture was heated at 80 °C overnight. An additional portion of potassium rerr-butoxide
(0.34 g, 3 mmol, 0.5 equiv.) was then added and the mixture was stirred at 80 °C an
additional 4 h. The mixture was cooled to 0 °C with an ice/water bath, then water

40

BAYER 18

(approx. 1 mL) was slowly added drop wise. The organic layer was extracted with EtOAc
(3 x 10 mL). The combined organic layers were washed with a saturated NaCl solution
(20 mL), dried (MgSCU) and concentrated under reduced pressure. The brown oily
residue was purified by column chromatography (SiCh; 30% EtOAc/ 70% pet ether) to
afford 4-(4-(2-(iV-{2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear
light brown oil (0.99 g, 38%).

A18. Synthesis of 2-PryidinecarboxyIate Esters via Oxidation of 2-

Methylpyridines. Synthesis of 4-(5-(2-

methoxycarbonyl)pyridy!oxy)aniline.

Step 1. 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene.

A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), l-fluoro-4-nitrobenzene
(9.8 mL, 91.6 mmol, 1.0 equiv.), K 2 C0 3 (25 g, 183 mmol, 2.0 equiv.) in DMF (100 mL)
was heated at the reflux temperature overnight. The resulting mixture was cooled to
room temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL).
The combined organic layers were sequentially washed with water (2 x 100 mL) and a
saturated NaCl solution ((100 mL), dried (MgSO<(.) and concentrated under reduced
pressure to give 4-(5-(2-methyl)pyridyloxy)-l-nitrobenzene as a brown solid (12.3 g).

Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-l-nitrobenzene.

A mixture of 4-(5-(2-methyl)pyridyloxy)-l -nitrobenzene (1.70 g, 7.39 mmol) and
selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the
reflux temperature for 5 h, then cooled to room temperature. The resulting slurry was
filtered , then concentrated under reduced pressure. The residue was dissolved in MeOH
(100 mL). The solution was treated with a cone HC1 solution (7 mL), then heated at the
reflux temperature for 3 h, cooled to room temperature and concentrated under reduced
pressure. The residue was separated between EtOAc (50 mL) and a IN NaOH solution

41

BAYER 13

I..,,*

(50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined
organic layers were sequentially washed with water (2 x 50 mL) and a saturated NaCl
solution (50 mL), dried (MgS0 4 ) and concentrated under reduced pressure. The residue
was purified by column chromatography (Si0 2 ; 50% EtO Ac/50% hexane) to afford 4-(5-
(2-methoxycarbonyl)pyridyloxy)-l-nitrobenzene (0.70 g).

r ii

.OMe

H 2 N

O

Step 3. Synthesis of 4-(S-(2-Methoxycarbonyl)pyridyloxy)aniline.

A slurry of 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-nitrobenzene (0.50 g) and 10% Pd/C
(0.050 g) in a mixture of EtO Ac (20 mL) and MeOH (5 mL) was placed under a H 2
10 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of
Celite®, and the filtrate was concentrated under reduced pressure. The residue was
purified by column chromatography (Si0 2 ; 70% EtOAc/30% hexane) to give 4-(5-(2-
methoxycarbonyl)pyridyloxy)aniline (0.40 g). -

15 A19. _ Synthesis of co-Sulfonylphenyl Anilines. Synthesis of 4-(4-

Methylsulfonylphenyoxy)aniline.

o 2 n ^ ^
o o

Step 1. 4-(4-Methylsulfonylphenoxy)-l-nitrobenzene: To a solution of 4-(4-
methylthiophenoxy)-! -nitrobenzene (2.0 g, 7.7 mmol) in CH 2 C1 2 (75 mL) at 0 °C was
20 slowly added m-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at room
temperature for 5 h. The reaction mixture was treated with a IN NaOH solution (25 mL).
The organic layer was sequentially washed with a IN NaOH solution (25 mL), water (25
mL) and a saturated NaCl solution (25 mL), dried (MgS0 4 ), and concentrated under
reduced pressure to give 4-(4-methylsulfonylphenoxy)-l -nitrobenzene as' a solid (2.1 g).

25

42

BAYER 13

Step 2. 4-(4-Methylsulfonylphenoxy)-l-aniline: 4-(4-Methylsulfonylphenoxy)-l-
nitrobenzene was reduced to the aniline in a manner analogous to that described in
Method Al 8, step 3.

B. Synthesis of Urea Precursors

Bl. General Method for the Synthesis of Isocyanates from Anilines Using

CDI. Synthesis of 4-Bromo-3-(trifhioromethyl)phenyl Isocyanate.

Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)aniline HC1 salt

To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et 2 0 (500 mL)
was added an HC1 solution (1 M in Et 2 0; 300 mL) dropwise and the resulting mixture
was stirred at room temp, for 16 h. The resulting pink-white precipitate was removed by
filtration and washed with Et 2 0 (50 mL) and to afford 4-bromo-3-
(trifluoromethyl)aniline HC1 salt (73 g , 98%).

Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate

A suspension of 4-bromo-3-(trifluoromethyl) aniline HC1 salt (36.8 g, 133 mmol) in
toluene (278 mL) was treated with trichloromethyl chloroformate dropwise and the
resulting mixture was heated at the reflux temp, for 18 h. The resulting mixture was
concentrated under reduced pressure. The residue was treated with toluene (500 mL),
then concentrated under reduced pressure. The residue was treated with CH 2 C1 2 (500
mL), then concentrated under reduced pressure. The CH 2 C1 2 treatment/concentration
protocol was repeated and resulting amber oil was stored at -20 °C for 16 h, to afford 4-
bromo-3-(trifluoromethyl)phenyl isocyanate as a tan solid (35.1 g, 86%): GC-MS m/z
265 CM*).

.43

BAYER 18

C. Methods of Urea Formation

Cla. General Method for the Synthesis of Ureas by Reaction of an

Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3-
(trifluoromethyl)phenyl)-iV , -(4-(2-(iV-methylcarbamoyl)-4-

pyridyIoxy)phenyI) Urea
CF 3

N N
H H

NHMe

A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in
CH2CI2 (35 mL) was added dropwise to a suspension of 4-(2-(Af-methylcarbamoyl)-4-
pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH 2 C1 2 (35 mL) at 0 °C.

10 The resulting mixture was stirred at room temp, for 22 h. The resulting yellow solids
were removed by filtration, then washed with CH2CI2 (2 x 30 mL) and dried under
reduced pressure (approximately 1 mmHg) to afford iV-(4-chloro-3-
(trifluoromethyl)phenyl)-iV'-(4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)phenyl) urea as an
off-white solid (28.5 g, 93%): mp 207-209 °C; 'H-NMR (DMSO-dO 5 2.77 (d, 7=4.8 Hz,

15 3H), 7.16 (m, 3H), 7.37 (d, 7=2.5 Hz, Hi), 7.62 (m, 4H), 8.11 (d, 7=2.5 Hz, 1H), 8.49 (d,
7=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465
((M+H) + ).

Clb. General Method for the Synthesis of Ureas by Reaction of an

20 Isocyanate with an Aniline. Synthesis of N-(4-Bromo-3-

(trifluoromethyl)phenyl)-iV ; '-(4-(2-(A^-methylcarbamoyl)-4-

pyridyloxy)phenyl) Urea

CF 3 O

H H

A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method Bl, Step 2; 8.0 g,
25 30.1 mmol) in CH 2 C1 2 (80 mL) was added dropwise to a solution of A-(2-(N-
methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in

44

BAYER 18

CH 2 C1 2 (40 mL) at 0 °C. The resulting mixture was stirred at room temp, for 16 h. The
resulting yellow solids were removed by filtration, then washed with CH2CI2 (2 x 50 mL)
and dried under reduced pressure (approximately 1 rnrnHg) at 40 °C to afford ^-(4-
bromo-3-(trifluoromethyl)phenyl)-A r '-(4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)phenyl)

5 urea as a pale-yellow solid (13.2 g, 90%): mp 203-205 °C; X H-NMR (DMSO-g*) 5 2.77
(d, 7=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, 7=2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d, 7=8.8 Hz,
■ 1H), 8.11 (d, 7=2.5 Hz, 1H), 8.49 (d, 7=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s,
1H); HPLC ES-MS m/z 509 ((M+H) + ).

10 Clc. General Method for the Synthesis of Ureas by Reaction of an

Isocyanate with an Aniline. Synthesis of A^-(4-Chloro-3-
(trifluoromethyl)phenyl)-A r '-(2-methyl-4-(2-(N-methylcarbamoyl)(4-

pyridyloxy))phenyl) Urea

NHMe

15 A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5;
0.11 g, 0.45 mmol) in CH 2 C1 2 (1 mL) was treated with Et 3 N (0.16 mL) and 4-chloro-3-
(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution
was stirred at room temp, for 6 d, then was treated with water (5 mL). The aqueous layer
was back-extracted with EtOAc (3x5 mL). The combined organic layers were dried

20 (MgS0 4 ) and concentrated under reduced pressure to yield A r -(4-chloro-3-
(trifluoromethyl)phenyl)-/Y'-(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)

urea as a brown oil (0.11 g, 0.22 mmol): X H NMR (DMSO-de) 8 2.27 (s, 3H), 2.77 (d,
7=4.8 Hz, 3H), 7.03 (dd, 7=8.5, 2.6 Hz, 1H), 7.11 (d, 7=2.9 Hz, 1H), 7.15 (dd, 7=5.5, 2.6,
Hz, 1H), 7.38 (d, 7=2.6 Hz, 1H), 7.62 (app d, 7=2.6 Hz, 2H), 7.84 (d, 7=8.8 Hz, 1H), 8.12
25 (s, 1H), 8.17 (s, 1H); 8.50 (d, 7=5.5 Hz, 1H), 8.78 (q, 7=5.2, 1H), 9.52 (s, 1H); HPLC ES-
MS m/z 479 ((M+H) + ).

45

BAYER 18

Cld.

General Method for the Synthesis of Ureas by Reaction of an
Isocyanate with an Aniline. Synthesis of iV-(4-Chlo ro-3-
(trifluoromethyl)phenyl)-iV : '-(4-aminophenyl) Urea

H H

To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in
CH2CI2 (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The
resulting mixture was stirred at room temp, for 1 h, treated with CH2CI2 (100 mL), and
concentrated under reduced pressure. The resulting pink solids were dissolved in a
mixture of EtOAc (110 mL) and MeOH (15mL), and the clear solution was washed with
a 0.05 N HC1 solution. The organic -layer was concentrated under reduced pressure to
afford impure iV-(4-chloro-3-(trifluoromethyl)phenyl)-iV'-(4-arninophenyl) urea (3.3 g):
TLC (100% EtOAc) R/0.72.

Cle. General Method for the Synthesis of Ureas by Reaction of an

To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH2CI2 (30 mL) was
added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was
stirred at room temp, overnight. The resulting slurry was diluted with CH2CI2 (50 mL)
and filtered to afford A r -(4-chloro-3-(trifIuoromethyl)phenyl)-A r '-(4-
ethoxycarbonylphenyl) urea as a white solid (5.93 g, 97%): TLC (40% EtOAc/60%
hexane) R/0.44.

Isocyanate with an Aniline. Synthesis of iV-(4-Chloro-3-
(trifluoromethyl)phenyl)-A'' , -(4-ethoxycarbonylphenyl) Urea

H

H

46

BAYER 18

Clf. General Method for the Synthesis of Ureas by Reaction of an

Isocyanate with an Aniline. Synthesis of 7V-(4-Chloro-3-
(trifluoromethyl)phenyl)- N'- (3-carboxyphenyI) Urea

cu

""OH

H H

5 To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21g, 5.46 mmol) in
CH 2 C1 2 (8 mL) was added 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76
.mmol) and the resulting mixture was stirred at room temp, overnight, then treated with
MeOH (8 mL), and stirred an additional 2 h. The resulting mixture was concentrated
under reduced pressure. The resulting brown solids were triturated with a 1:1

10 EtOAc/hexane solution to give iV-(4-chloro-3-(trifluoromethyl)phenyl)-iV r '-{3-
carboxyphenyl) urea as an off-white solid (1.21 g, 76%).

C2a. General Method for Urea Synthesis by Reaction of an Aniline with

A^iV'-Carbonyl Diimida2ole Followed by Addition of a Second
15 Aniline. Synthesis of N-(2-Methoxy-5-(trifluoromethyl)phenyl)-A r: '-(4-

(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
CF 3 O

N x N U u

— , . H H '
OMe

To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH2CI2 (15 mL) at
0 °C was added CDI (0.13 g). The resulting solution was allowed to warm to room temp.

20 over 1 h, was stirred at room temp, for 16 h, then was treated with 4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow solution was
stirred at room temp, for 72 h, then was treated with H?0 (125 mL). The. resulting
aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organics were
washed with a saturated NaCl solution (100 mL), dried (MgS0 4 ) and concentrated under

25 reduced pressure/ The residue was triturated (90% EtO Ac/10% hexane). The resulting
white solids were collected by filtration and washed with EtOAc. The filtrate was

47

BAYER IS

concentrated under reduced pressure and the residual oil purified by column
chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane to
100% EtOAc) to give iV-(2-methoxy-5-(trifluoromethyl)phenyl)-A r '-(4-(2-(iV-
methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a light tan solid (0.098 g, 30%): TLC
5 (100% EtOAc) R/0.62; l K NMR (DMSO-d 6 ) 8 2.76 (d, 7=4.8 Hz, 3H), 3.96 (s, 3H), 7.1-
. 7.6 and 8.4-8.6 (m, 11H), 8.75 (d, 7=4.8 Hz, 1H), 9.55 (s, 1 H); FAB-MS m/z 461
((M+H) + ).

C2b. General Method for Urea Synthesis by Reaction of an Aniline with

10 N,N'-Carbonyl Diimidazole Followed by Addition of a Second

Aniline. Symmetrical Urea's as Side Products of a fyiV'-Carbonyl
Diimidazole Reaction Procedure. Synthesis of Bis(4-(2-(iV-
methylcarbamoyl)-4-pyridyloxy)phenyl) Urea

~N N
H H

15 To a stirring solution of 3-arnino-2-methoxyquinoline (0.14 g) in anhydrous CH2CI2 (15
mL) at 0 C was added CDI (0.13 g). The resulting solution was allowed to warm to room
temp, over 1 h then was stirred at room temp, for 16 h. The resulting mixture was treated
with 4-(2-(7Y-memylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow
solution stirred at room temp, for 72 h, then was treated with water (125 mL). The

20 resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined
organic phases were washed with a saturated NaCl solution (100 ml), dried (MgSCU) and
concentrated under reduced pressure. The residue was triturated (90% EtOAc/10%
hexane). The resulting white solids were collected by filtration and washed with EtOAc
to give bis(4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.081 g, 44%): TLC

25 (100% EtOAc) R/0.50; *H NMR (DMSO-dg) 5 2.76 (d, 7=5.1 Hz, 6H), 7.1-7.6 (m, 12H),
8.48 (d, 7=5.4 Hz, 1H), 8.75 (d, 7=4.8 Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m/z 513
. ((M+H) + ).

48

BAYER 18

C2c. General Method for the Synthesis of Ureas by Reaction of an

Isocyanate with an Aniline. Synthesis of iV-(2-Methoxy-5-
(trifluoromethyl)phenyl-N : '-(4-(l,3-dioxoisoindolin-5-yioxy)phenyl)
Urea

CF 3

9 rr°r^

OMe H H ^ — NH

O

To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47
mmol) in CH2CI2 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-l,3-dione (Method
A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h,
then was treated with CH2CI2 (10 mL) and MeOH (5 mL). The resulting mixture was
sequentially washed with a IN HC1 solution (15 mL) and a saturated NaCl solution (15
mL), dried (MgS04.) and concentrated under reduced pressure to afford A r -(2-methoxy-5-
(trifluoromethyl)phenyl-iV'-(4-(l,3-dioxoisoindohn-5-yloxy)phenyl) urea as a white solid
(0.2 g, 96%): TLC (70% EtOAc/30% hexane) R/0.50; l H NMR (DMSO-d 6 ) 8 3.95 (s,
3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H),
9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS 472.0 ((M+Hf , 100%).

C2d. General Method for Urea Synthesis by Reaction of an Aniline with

iVjA^-Carbonyl Diimidazole Followed by Addition of a Second
Aniline. Synthesis of N-(5-(tert~Butyl)-2-(2,S-
dimethyIpyrroIyl)phenyI)-/V'-(4-(2-(/V-methylcarbamoyl)-4-
pyridyloxy)phenyl) Urea

To a stirring solution of CDI (0.21g, 1.30 mmol) in CH 2 C1 2 (2 mL) was added 5-{tert-
butyl)-2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one

49

BAYER 18

portion. The resulting mixture was stirred at room temp, for 4 h, then 4~(2-(N-
methylcarbamoyl)-4-pyridyloxy)aniline (0.065 g, 0.267mmol) was then added in one
portion. The resulting mixture was heated at 36 °C overnight, then cooled to room temp,
and diluted with EtOAc (5 mL). The resulting mixture was sequentially washed with
water (15 mL) and a IN HC1 solution (15mL), dried (MgS0 4 ), and filtered through a pad
of silica gel (50 g) to afford iV-(5-(rerr-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)- J Y'-(4-(2-
(jV-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a yellowish solid (0.033 g, 24%):
TLC (40% EtO Ac/60% hexane) R 7 0.24; l H NMR (acetone-de) 5 1.37 (s, 9H), 1.89 (s,
6H), 2.89 (d, /=4.8Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m,
3H), 8.43 (d, 7=5.4Hz, 1H), 8.57 (d, 7=2.1Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512
((M+H) + , 100%).

C3. Combinatorial Method for the Synthesis of Diphenyl Ureas Using

Triphosgene

One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This
solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this
was added a bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL,
0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2
equiv.). The vial was capped and heat at 80 °C for 5 h, then allowed to cool to room
temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane,
0.5 mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2
mL, 1.2 equiv.). The resulting mixture was heated at 80 °C for 4 h, cooled to room
temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated
under reduced pressure and the products were purified by reverse phase HPLC.

50

BAYER 18

C4. General Method for Urea Synthesis by Reaction of an Aniline with Phosgene
Followed by Addition of a Second Aniline. Synthesis of /V-(2-Methoxy-5-
(trifluoromethyl)phenyl)-A r, -(4-(2-(A^-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea

.5 To a stirring solution of phosgene (1.9 M in toluene; 2:07 mL0.21g, 1.30 mmol) in
CH 2 C1 2 (20 mL) at 0 °C was added anh pyridine (0.32 mL) followed by 2-methoxy-5-
(trifluoromethyl)aniline (0.75 g). The yellow solution was allowed to warm to room
temp during which a precipitate formed. The yellow mixture was stirred for 1 h, then
concentrated under reduced pressure. The resulting solids were treated with anh toluene

10 (20 mL) followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (prepared as
described in Method A2; 0.30 g) and the resulting suspension was heated at 80 °C for 20
h, then allowed to cool to room temp. The resulting mixture was diluted with water (100
mL), then was made basic with a saturated NaHC0 3 solution (2-3 mL). The basic
solution was extracted with EtOAc (2 x 250 mL). The organic layers were separately

15 washed with a saturated NaCl solution, combined, dried (MgS0 4 ), and- concentrated
under reduced pressure. The resulting pink-brown residue was dissolved in MeOH and
absorbed onto Si0 2 (100 g). Column chromatography (300 g Si0 2 ; gradient from 1%
Et 3 N/33% EtOAc/66% hexane to 1% Et 3 N/99% EtOAc to 1% Et 3 N/20% MeOH/79%
EtOAc) followed by concentration under reduced pressure at 45 °C gave a warm

20 concentrated EtOAc solution, which was treated with hexane (10 mL) to slowly form
crystals of iV-(2-methoxy-5-(trifluoromethyl)phenyl)-iV"-(4-(2-(iV-methylcarbamoyl)-4-
pyridyloxy)phenyl) urea (0.44 g): TLC (1% Et 3 N/99% EtOAc) R/0.40.

51

BAYER 18

D. Interconversion of Ureas

Dla. Conversion of co-Aminophenyl Ureas into co-(Aroylamino)phenyl

Ureas. Synthesis of A r -(4-Chioro-3-((trifluoromethyl)phenyl)-A^ , -(4-(3-
methoxycarbonylphenyl)carboxyaminophenyl) Urea

H H

To a solution of iV-(4-chloro-3-((trifluoromethyl)phenyl)-iV'-(4-aminophenyl) urea
(Method Cld; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmol),
HOBT«H 2 0 (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL, 3.03 mmol) in
DMF (8 mL) was added EDCI -HC1 (0.29 g, 1.52 mmol). The resulting mixture was
stirred at room temp, overnight, diluted with EtOAc (25 mL) and sequentially washed
with water (25 mL) and a saturated NaHC0 3 solution (25 mL). The organic layer was
dried (Na 2 SC>4) and concentrated under reduced pressure. The resulting solids were
triturated with an EtOAc solution (80% EtOAc/20% hexane) to give N-(4-chloro-3-
((trinuoromemyl)phenyl)-A r '-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea
(0.27 g, 43%): mp 121-122; TLC (80% EtOAc/20% hexane) R/0.75.

Dlb. Conversion of co-Carboxyphenyl Ureas into co-(Arylcarbamoyl)phenyl

Ureas.. Synthesis of A^-(4-Chloro-3-((trifluoromethyl)phenyl)-N , -(4-(3-
methylcarbamoylphenyl)carbamoylphenyl) Urea

NHMe

H H

To a solution of iV-(4-chloro-3-((trifluoromethyl)phenyl)-iV'-(4-(3-
methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-
methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBT-H 2 0 (0.14 g, 1.07 mmol), and N-
methylmorpholine (0.5mL, 1.07 mmol) in DMF (3 mL) at 0 °C was added EDCI'HCl
(0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to room temp, and was
stirred overnight. The resulting mixture was treated with water (lOmL), and extracted

52

BAYER 18

with EtOAc (25 mL). The organic phase was concentrated under reduced pressure. The
resulting yellow solids were dissolved in EtOAc (3 mL) then filtered through a pad of
silica gel (17 g, gradient from 70% EtOAc/30% hexane to 10% MeOH/90% EtOAc) to
give iV-(4-chloro-3-((trifluoromethyl)phenyl)-iv"-(4-(3-
5 methyIcarbamoylphenyl)carbamoylphenyl) urea as a white solid (0.097 g, 41%): mp 225-
229; TLC (100% EtOAc) R/0.23.

Combinatorial Approach to the Conversion of co-Carboxyphenyl
Ureas into co-(Arylcarbamoyl)phenyl Ureas. Synthesis of N-(4-
Chloro-3-((trifluoromethyI)phenyI)-/Y'-(4-(N-(3-(N-(3-
pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) Urea

H H

A mixture of iV-(4-chloro-3-((trifIuoromethyl)phenyl)-iV'-(3-carboxyphenyl) urea
15 (Method Clf; 0.030 g, 0.067 mmol) and iV-cyclohexyl-./V'-
(methylpolystyrene)carbodiimide (55 mg) in 1,2-dichloroethane (1 mL) was treated with
a solution of 3-aminopyridine in CH 2 C1 2 (1 M; 0.074 mL, 0.074 mmol). (In cases of
insolubility or turbidity, a small amount of DMSO was also added.) The resulting
mixture was heated at 36 °C overnight. Turbid reactions were then treated with THF (1
20 mL) and heating was continued for 18 h. The resulting mixtures were treated with
poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture was stirred at 36
°C for 72 h, then cooled to room temp, and filtered. The resulting solution was filtered
through a plug of silica gel (1 g). Concentration under reduced pressure afforded iV-(4-
chloro-3-((trifluoromethyl)phenyl)-iV'-(4-(N-(3-(N-(3-
25 pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70%
EtO Ac/30% hexane) R/0.12.

Die.

10

53

BAYER 18

D2. Conversion of coCarboalkoxyaryl Ureas into co-Carbamoylaryl

Ureas. Synthesis of iV-{4-Chloro-3-((trifluororaethyl)phenyl)-A^ , -(4-(3-
methylcarbamoylphenyl)carboxyaminophenyl) Urea

NHMe

H H

To a sample of N-(4-chloro-3-((trifluoromethyl)phenyl)-A r '-(4-(3-carbomethoxyphenyl)
carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1
mL, 1.7 mmol) and the resulting mixture was stirred at room temp, overnight, then
concentrated under reduced pressure to give iV-(4-chloro-3-((trifluoromethyl)phenyl)-A^'-
(4-(3-methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC
(100%EtOAc)R/0.35.

D3. Conversion of co-Carboalkoxyaryl Ureas into co-Carboxyaryl Ureas.

Synthesis of A r -(4-Chloro-3-((trifluoromethyl)phenyl)-A r '-(4-
carboxyphenyl) Urea

H H

To a slurry of iV-(4-chloro-3-((trifluoromethyl)phenyl)-A r '-(4-ethoxycarbonylphenyl) urea
(Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH
solution (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated at the reflux temp,
for 12 h, cooied to room temp., and concentrated under reduced pressure. The residue
was diluted with water (50 mL), then treated with a 1 N HC1 solution to adjust the pH to
2 to 3. The resulting solids were collected and dried under reduced pressure to give N-(4-
chloro-3-((trifluoromethyl)phenyl)-A/"-(4-carboxyphenyl) urea as a white solid (5.05 g,

92%).

54

BAYER 18

D4. General Method for the Conversion of co-Alkoxy Esters into co-Alkyl Amides.
Synthesis of A^-(4-Chloro-3-((trifluoromethyI)phenyl)-Af'-((4-(3-(5-(2-
dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) Urea

CF 3 O

N

5 Step 1. Synthesis of iV-(4-Chloro-3-(trifluoromethyl)phenyl)-iY'-((4-(3-(5-

carboxypyridyl) oxyphenyl) Urea

iV-(4-Chloro-3-(trifluoromethyl)phenyl)-iV'-((4-(3-(5-

methoxycarbonylpyridyl)oxyphenyl) urea was synthesized from 4-chloro-3-
(trifluoromethyl)phenyl isocyanate and 4-(3-(5-methoxycarbonylpyridyl) oxyaniline
10 ■ (Method A14, Step 2) in a manner analogous to Method Cla. A suspension of iV-(4-
chloro-3-(trifluoromethyl)phenyl)-A r '-((4-(3-(5-methoxycarbonylpyridyl)oxyphenyl) urea
(0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5
mmol) in water (1 mL) and was stirred at room temp, for 1 h. The resulting mixture was
adjusted to pH 5 with a 1 N HC1 solution. The resulting precipitate was removed by
15 filtration and washed with water. The resulting solids were dissolved in EtOH (10 mL)
and the resulting solution was concentrated under reduced pressure. The
EtOH/concentration procedure was repeated twice to give A r -(4-chloro-3-
(trifluoromethyl)phenyl)-iV'-((4-(3-(5-carboxypyridyl) oxyphenyl) urea (0.18 g, 71%).

CF 3 ' . 9 1

N

20 Step 2. Synthesis of A r -(4-chloro-3-(trifIuoromethyl)phenyl)-^/ , -((4-(3-(5-(2-

dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea

A . mixture of Af-(4-chloro-3-(trifluoromethyl)phenyl)-A r '-((4-(3-(5-

carboxypyridyl)oxyphenyl) urea (0.050 g, 0.011 mmol), A^,iV-dimethylethylenediamine
(0.22 mg, 0.17 mmol), HOBT. (0.028 g, 0.17 mmol), iV-methylmorpholine. (0.035 g, 0.28
25 mmol), and EDCI'HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temp,
overnight. .The resulting solution was separated between EtOAc (50 mL) and water (50

55

BAYER 18

mL). The organic phase was washed with water (35 mL), dried (MgSCU) and
concentrated under reduced pressure. The residue was dissolved in a minimal amount of
CH2CI2 (approximately 2 mL). The resulting solution was treated with Et20 dropwise to
give A r -(4-chloro-3-(trifluoromethyl)phenyl)-A r '-((4-(3-(5-(2-
5 dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea as a white precipitate (0.48 g,
84%: l R NMR (DMSO-a*) 8 2.10 s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m,
3H), 8.05 (s, 1H), 8.43 (s, 1H), 8.58 (t, 1H), 8.69 (s, 1H), 8.90 (s, 1H), 9.14 (s, 1H);
HPLC ES-MS m/z 522 ((M+H) + ).

10 D5. General Method for the Deprotection of iV-(co-Silyloxyalkyl)amides.

Synthesis of A^-(4-Chloro-3-((trifluoromethyl)phenyl)-iV'-(4-(4-(2-(N-
(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) Urea.
CF 3 O \

H H

To a solution of /v , -(4-chloro-3-((trifluoromethyl)phenyl)-iV , -(4-(4-(2-(iV-(2-
15 triisopropylsilyloxy) ethylcarbamoyl)pyridyloxyphenyl) urea (prepared in a manner
analogous to Method Cla; 0.25 g, 0.37 mmol) in anh THF (2 mL) was
tetrabutylamrnonium fluoride (1.0 M in THF; 2 mL). The mixture was stirred at room
temperature for 5 min, then was treated with water (10 mL). The aqueous mixture was
extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (MgSCU)
20 and concentrated under reduced pressure. The residue was purified by column
chromatography (Si0 2 ; gradient from 100% hexane to 40% EtOAc/60% hexane) to give
A r -(4-chloro-3-((trifluoromethyl)phenyl)-A r '-(4-(4-(2-(iV-(2-
hydroxy)eth.ylcarbamoyl)pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).

25 Listed below are compounds listed in the Tables below which have been

synthesized according to the Detailed Experimental Procedures given above:

56

BAYER IS

Syntheses of Exemplified Compounds

(see Tables for compound characterization)

5 Entry 1: 4-(3-A r -Methylcarbamoylphenoxy)aniline was prepared according to Method
A13. According to Method C3, 3-terr-butylaniline was reacted with
bis(trichloromethyl)carbonate followed by 4-(3-iV-Methylcarbamoyiphenoxy)aniline to
afford the urea.

10 Entry 2: 4-Fluoro-l -nitrobenzene and /7-hydroxyacetophenone were reacted according to
Method A13, Step 1 to afford the 4-(4-acetyIphenoxy)-l-nitrobenzene. 4-(4-
Acetylphenoxy)-l -nitrobenzene was reduced according to Method A13, Step 4 to afford
4-(4-acetylphenoxy)aniline. According to Method C3, 3-terr-butylaniline was reacted
with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the

15 urea.

Entry 3: According to Method C2d, 3-terr-butylaniline was treated with CDI, followed
by 4-(3-A/'-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared
according to Method A8, to afford the urea.

20

Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to 5-?ert-butyl-2-methoxyphenyl
isocyanate according to Method Bl. 4-(3-A r -Methylcarbamoylphenoxy)aniline, prepared
according to Method A13, was reacted with the isocyanate according to Method Cla to
afford the urea.

25

Entry 5: According to Method C2d, 5-ferr-butyl-2-methoxyaniline was reacted with CDI
followed by 4-(3-N-memylcarbamoyl)-4-rnethoxyphenoxy)aniline, which had been
prepared according to Method A8, to afford the urea.

57

BAYER 18

Entry 6: 5-(4-Aminophenoxy)isoindoline-l,3-dione was prepared according to Method
A3. According to Method 2d, 5-^-butyl-2-methoxyaniline was reacted with CDI
followed by 5-(4-aminophenoxy)isoindoline-l,3-dione to afford the urea.

5 Entry 7: 4-(l-Oxoisoindolin-5-yIoxy)aniline was synthesized according to Method A12.
According to Method 2d, 5-?err-butyl-2-methoxyaniline was reacted with CDI followed
by 4-(l-oxoisoindolin-5-yloxy)aniline to afford the urea.

Entry 8: 4-(3-A r -Methylcarbamoylphenoxy)aniline was synthesized according to Method
10 A13. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with
CDI followed by 4-(3-N-methylcarbamoylphenoxy)aniline to afford the urea.

Entry 9: ' 4-Hydroxyacetophenone was reacted with 2-chloro-5-riitropyridine to give 4-
(4-acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to
15 Method A8, Step 4, 4-(4-acetylphenoxy)-5-nitropyridine was reduced to 4-(4-
acetylphenoxy)-5-aminopyridine. 2-Methoxy-5-(trifluoromethyl)anilme was converted
to 2-methoxy-5-(trifiuoromethyl)phenyl isocyanate according to Method Bl. The
isocyanate was reacted with 4-(4-acetylphenoxy)-5-aminopyridine according to Method
Cla to afford the urea.

20

Entry 10: 4-Fluoro-l -nitrobenzene and p-hydroxyacetophenone were reacted according
to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-l-nitrobenzene. 4-(4-
Acetylphenoxy)-l-nitrobenzene was reduced according to Method A13, Step 4 to afford
4-(4-acetylphenoxy)aniline. According to Method C3, 5-(trifluoromethyl)-2-
25 methoxybutylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-
acetylphenoxy)aniline to afford the urea.

Entry 11: 4-Chloro-A r -methyl-2-pyridinecarboxamide, which was synthesized according
to Method A2, Step 3a, was reacted with 3-aminophenoI according to Method A2, Step 4
30 using DMAC in place of DMF to give 3-(-2-(iV-methylcarbamoyl)-4-pyridyloxy)anilme.
According to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with

58

BAYER 18

phosgene followed by 3-(-2-(jV-methvlcarbamoyl)-4-pvridyloxy)aniline to afford the
urea.

Entry 12: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia
5 according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
pyridinecarboxarnide was reacted with 3-aminophenol according to Method A2, Step 4
using DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According
to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene
followed by 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.

10

Entry 13: 4-Chloro-A r -methyl-2-pyridinecarboxamide was synthesized according to
Method A2, Step 3b. 4-Chloro-iV-methyl-2-pyridinecarboxamide was reacted with 4-
aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-
(2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-
15 (trifluoromethyl)aniline was reacted with CDI followed by 4-(2-(iV-methylcarbamoyl)-4-
pyridyloxy) aniline to afford the urea.

Entry 14: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia
according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
20 pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4
using DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According
to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed
by 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.

25 Entry 15: According to Method C2d, 5-(triflouromethyI)-2-methoxy aniline was reacted
with CDI followed by 4-(3-iV-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had
been prepared according to Method A8, to afford the urea.

Entry 16: 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized
30 according to Method A5. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. The isocyanate

59

BAYER IS

was reacted with 4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to
Method Clc to afford the urea.

Entry 17: 4-(2-(A r -Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized
5 according to Method A6. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(JV-
methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline according to Method Cla to afford the
urea.

10

Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-
chloro-Af-methyl-2-pyridinecarboxarnide, which had been .synthesized according to
Method A2, Step 3b, to give 3-(2-(iV-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline.
5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
15 methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-
methoxyphenyl isocyanate was reacted with 3-(2-(jV-methylcarbamoyl)-4-pyridyIoxy)-4-
methylaniline according to Method Cla to afford the urea.

- Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according
20 to Method A2, Step 3b. The resulting 4-chloro-iV-ethyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(7V-
ethylcarbamoyl)-4-pyridyloxy)aniline. 5-(TrifIuoromethyl)-2-methoxyaniline was
converted into 5-(trifluoro'methyl)-2-methoxyphenyl isocyanate according to Method Bl.
5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(7V-
25 ethylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the urea.

Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-
cUoro-N-methyl-2-pyridinecarboxarnide, which had been synthesized according to
Method A2, Step 3b, to give 4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline.
30 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyi)-2-
methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-

60

BAYER IS

methoxyphenyl isocyanate was reacted with 4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)-3-
chloroaniline according to Method Cla to afford the urea.

Entry 21: 4-(4-Methylthiophenoxy)-l-nitrobenzene was oxidized according to Method
5 A19, Step 1 to give 4-(4-methylsulfonylphenoxy)-l -nitrobenzene. The nitrobenzene was
reduced according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-l-aniline.
According to Method Cla, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted
with 4-(4-methylsulfonylphenoxy)-l-aniline to afford the urea.

10 Entry 22: 4-(3-carbamoylphenoxy)-l-nitrobenzene was reduced to 4-(3-
carbamoylphenoxy)aniline according to Method A15, Step 4. According to Method Cla,
5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-
carbamoylphenoxy)aniline to afford the urea.

15 Entry 23: 5-(4-Aminophenoxy)isoindoline-l,3-dione was synthesized according to
Method A3. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-
aminophenoxy)isoindoline-l ,3-dione according to Method CI a to afford the urea.

20

25

Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine
according to Method A2, Step 3b. The resulting 4-chloro-M^-dimethyl-2-
pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to
give 4-(2-(iV,iV-dimethylcarbamoyl)t4-pyridyloxy)aniline: 5-(Trifluoromethyl)-2-
methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate
according to Method Bl. 5-(Trifluoromethyl)-2 -methoxyphenyl isocyanate was reacted
with 4-(2-(iV,A r -dimethylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to
afford the urea.

61

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Entry 25: 4-(l-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12.
5-(Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-(l-
oxoisoindolin-5-yloxy)aniline according to Method C2d to afford the urea.

5 Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to
Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was
reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniIine, which
was converted to the 4-(4-(l-(iV-methoxy)iminoethyl)phenoxyaniline HC1 salt according
to Method A16. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-

10 (trifluoromethyl)-2 -methoxyphenyl isocyanate according to Method Bl. 5-
[Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(l-(7V-
methoxy)iminoethyl)phenoxyaniline HC1 salt to Method CI a to afford the urea.

Entry 27: 4-Chloro-A r -methylpyridinecarboxamide was synthesized as described in
IS Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according
to Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-
• methoxyphenyl isocyanate was reacted with 4-(4-(2-(iV-

20 methylcarbamoyl)phenyIthio)aniMne according to Method Cla to afford the urea.

Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione was synthesized
according to Method A9. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-
25 (Trifluoromethyl)-2 -methoxyphenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-
methylisoindoline-l,3-dione according to Method Cla to afford the urea.

Entry 29: 4-Chloro-A/Vmethylpyridinecarboxamide was synthesized as described in
Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according
30 to Method A2, Step 4 to give 3-(4-(2-(iV-methylcarbamoyI)phenylthio)aniline. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyI)-2-

62

BAYER 18

methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-
methoxyphenyl isocyanate was reacted with 3-(4-(2-(iV-
methylcarbamoyl)phenylthio)aniline according to Method CI a to afford the urea.

Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine
according to Method A2, Step 3b. The resulting 4-chloro-JV-isopropyl-2-
pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to
give 4-(2-(A r -isopropylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-
methoxy aniline was converted into 5-(trifluoromethyl)-2 -methoxyphenyl isocyanate
according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted
with 4-(2-(iV-isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to
afford the urea.

Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to
Method A 14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. iV-(5-
(Trifluoromethyl)-2-methoxyphenyl)-iV'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)
urea was saponified according to Method D4, Step 1, and the corresponding acid was
coupled with 4-(2-aminoethyl)morpholine to afford the amide according to Method D4,
Step 2.

Entry 32: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to
Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)anihne according to Method Cla to afford the urea. N-(5-
(Trifluoromethyl)-2-methoxyphenyl)-iV'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)

urea was saponified according to Method D4, Step 1, and the corresponding acid was
coupled with methylamine according to Method D4, Step 2 to afford the amide.

63

BAYER 18

Entry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to
Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyi)pyridyloxy)aniline according to Method Cla to afford the urea. iV-(5-
(Trifluoromethyl)-2-methoxyphenyl)-iV'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)
urea was saponified according to Method D4, Step 1, and the corresponding acid was
coupled with N,iV-dirnethylethylenedi amine according to Method D4, Step 2 to afford the
amide.

Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-
(Trifiuoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was
reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to
afford iV-(5-(trifluoromethyl)-2-methoxypheny.l)-iV'-(3-carboxyphenyl) urea, which was
coupled with 3-aminopyridine according to Method Die.

Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was
reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to
afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was
coupled with iV-(4-fluorophenyl)piperazine according to Method Die.

Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was
reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to
afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-iV'-(3-carboxyphenyl) urea, which was
coupled with 4-fluoroaniline according to Method Die.

64

BAYER 18

Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was
reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to
afford ^-(5-(ttifluoromethyl)-2-mcthoxyphenyl)-N'-(3K:aiboxyphenyl) urea, which was
coupled with 4-(dimethylamino)aniline according to Method Die.

Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was
reacted with 5-(trifluoro'methyl)-2-methoxyphenyl isocyanate according to Method Clf to
afford ^-(5-(trifluoromethyl)-2-methoxyphenyl)-iV'-(3^arboxyphenyl) urea, which was
coupled with 5-amino-2-methoxypyridine according to Method Die.

Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was
reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to
afford Ar.(5-(trifluoromethyl)-2-methoxyphenyl)-A r '-(3-carboxyphenyl) urea, which was
coupled with 4-morpholinoaniline according to Method Die.

Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was
reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to
afford iV-(5-('trifluoromethyl)-2-methoxyphenyl)-iV'-(3-carboxyphenyl) urea, which was
coupled with iV-(2-pyridyl)piperazine according to Method Die.

Entry 41: 4-(3-(iV-Methylcarbamoyl)phenoxy)aniline was synthesized according to
Method A13. According to Method C3, 4-chloro-3-Ctrifluoromethyl)aniline was

65-

BAYER 18

converted to the isocyanate, then reacted with 4-(3-(A r -Methylcarbamoyl)phenoxy)aniline
to afford the urea.

Entry 42: 4-(2-iV-Methylcarbamyl-4-pyridyloxy)aniline was synthesized according to
5 Method A2. 4-Chloro-3-(trifluoromethyl)phenyI isocyanate was reacted with 4-(2-A r -
methylcarbamyl-4-pyridyloxy)aniline according to Method CI a to afford the urea.

Entry 43: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia
according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
10 pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to
form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method CI a, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-
pyridyloxy)aniline to afford the urea.

15 Entry 44: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia
according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxarnide. 4-Chloro-2-
pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 to
form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-carbamoyl-4-

20 pyridyloxy)aniline to afford the urea.

Entry 45: 4-Chloro-N-methyl -2 -pyridinecarboxamide, which was synthesized according
to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4
to form 3-(-2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-
25 chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(iV-methylcarbamoyl)-
4-pyridyloxy)aniline to afford the urea.

Entry 46: 5-(4-Aminophenoxy)isoindoline-l,3-dione was synthesized according to
Method A3. According to Method Cla, 4-chloro-3-(trifIuoromethyl)phenyl isocyanate
30 was reacted with 5-(4-aminophenoxy)isoindoline-l,3-dione to afford the urea.

66

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Entry 47: 4-(2-(iV-Met±iylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized
according to Method A5. According to Method Clc, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 5-(4-aminophenoxy)isoindoiine-l,3-dione to afford the urea.

Entry 48: 4-(3-iV-Methylsulfamoyl)phenyloxy)aniline was synthesized according to
Method A15. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate
was reacted with 4-(3-iV-methylsulfamoyl)phenyloxy)aniline to afford the urea.

Entry 49: 4-(2-(iY-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized
according to Method A6. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to
afford the urea.

Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-
chloro-jV-methyl-2-pyridinecarboxamide, which had been synthesized according to
Method A2, Step 3b, to give 3-(2-(iV-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline.
According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
with 3-(2-(iV-methylcarbambyl)-4-pyridyloxy)-4-methylaniline to afford the urea.

20 Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according
to Method A2, Step 3b. The resulting 4-chloro-iV-ethyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(iV-
ethylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-

25 pyridyloxy)aniline to afford the urea.

Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-
chloro-iV-methyl-2-pyridinecarboxamide, which had been synthesized according to
Method A2, Step 3b, to give 4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline.
30 According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
with 4-(2-(^-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.

67

BAYER 18

Entry 53: 4-(4-Methylthiophenoxy)-l -nitrobenzene was oxidized according to Method
A19, Step 1 to give 4-(4-methylsulfonylphenoxy)-l-nitrobenzene. The nitrobenzene was
reduced according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-l-aniline.
5 According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
with 4-(4-methylsulfonylphenoxy)-l-aniline to afford the urea.

Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to
Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide. iV-Methyl-4-
'% 10 bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to
''G afford 4-(4-(N-methylsulfamoyl)phenoxy)benzene. 4-(4-(iV-

fjij Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(iV-

'% methylsulfamoyl)phenoxy)-l-nitrobenzene according to Method A15, Step 3. 4-(4-(iV-

H n Methylsulfamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(4-N-

h% 15 methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According to
Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-iV-

m

' % 4 methylsulfamoyl)phenyloxy)aniline to afford the urea.

Entry 55: 5-Hydroxy-2-methylpyridine was coupled with l-fluoro-4-nitrobenzene
20 according to Method A18; Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene.
^ The methylpyridine was oxidized according to the carboxylic acid, then esterified

according to Method A18, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-
nitrobenzene. The nitrobenzene was reduced according the Method A18, Step 3 to give
4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-
25 (trifluoromethyl)phenyl isocyanate according to Method Cla to afford the urea.

Entry 56: 5-Hydroxy-2-methylpyridine was coupled with l-fluoro-4-nitrobenzene
according to Method A18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene.
The methylpyridine was oxidized according to the carboxylic acid, then esterified
30 according to Method A18, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-
nitrobenzene. The nitrobenzene was reduced according the Method A18, Step 3 to give

63

BAYER 18

4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-
(trifluoromethyl)phenyl isocyanate according to Method Cla to give N-(4-chloro-3-
(trifluoromethyl)phenyl)-A r '-(4-(2-(methoxycarbonyl)-5-pyridyloxy)phenyl) urea. The
methyl ester was reacted with methylamine according to Method D2 to afford iV-(4-
chloro-3-(trifluoromethyl)phenyl)-A r '-(4-(2<iV-met±iylcarbamoyl)-5-pyridyloxy)phenyl)
urea.

Entry 57: A r -(4-Chloro-3-(trifluoromethyl)phenyl-A^'-(4-aminophenyl) urea was prepared
according to Method Cld. A r -(4-CWoro-3-(trifluoromethyl)phenyl-A r '-(4-arninophenyl)
urea was coupled with mono-methyl isophthalate according to Method Dla to afford the
urea.

Entry 58: A r -(4-Chloro-3-(trifluoromethyl)phenyl-A r '-(4-aminophenyl) urea was prepared
according to Method Cld. //-(4-Chloro-3-(trifluoromethyl)phenyl-//'-(4-aminophenyl)
urea was coupled with morco-methyl isophthalate according to Method Dla to afford N-
(4-chloro-3-(trifluoromethyl)phenyl-A'"-(4-(3-

methoxycarbonylphenyl)carboxyaminophenyl) urea. According to Method D2, N-(4-
chloro-3-(trifluoromethyl)phenyl-A r '-(4-(3-

methoxycarbonylphenyl)carboxyaminophenyl) urea was reacted with methylamine to
afford the corresponding methyl amide.

Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine
according to Method A2, Step 3b. The resulting 4-chloro-iV,A r -dimethyl-2-
pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to
give 4-(2-(A r ,A r -dimethylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-
chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(iV,iV-
dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to
Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was
reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was

69

BAYER 18

converted to the 4-(4-(l-(iV-methoxy)iminoethyl) phenoxyaniline HC1 salt according to
Method A16. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate
was reacted with 4-(4-acetylphenoxy)aniline to afford the urea.

5 Entry 61: 4-(3-Carboxyphenoxy)-l -nitrobenzene was synthesized according to Method
A13, Step 2. 4-(3-Carboxyphenoxy)-l -nitrobenzene was coupled with 4-(2-
aminoethyl)morpholine according to Method A13, Step 3 to give 4-(3-(iV-(2-
morpholinylethyl)carbamoyl)phenoxy)-l-nitrobenzene. According to Method A13 Step
4 > 4-(3-(7V-(2-morpholinylethyl)carbamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3-

10 (A^-(2-morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-
chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(iV-(2-
morpholinylethyl)carbamoyl)phenoxy)aniline to afford the urea.

Entry 62: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method
15 A13, Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with l-(2-
aminoethyl)piperidine according to Method A13, Step 3 to give 4-(3-(iV-(2-
piperidylethyl)carbamoyl)phenoxy)-l -nitrobenzene. According to Method A13 Step 4,
4-(3-(A r -(2-piperidylethyl)carbamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3-(iV-
(2-piperidylethyl)carbamoyl)phenoxy)aniline. ' According to Method Cla, 4-chloro-3-
20 (trifluoromethyl)phenyl isocyanate was reacte-d with 4-(3-(iV-(2-
piperidylethyl)carbamoyl)phenoxy)aniline to afford the urea.

Entry 63: 4-(3-Carboxyphenoxy)-l -nitrobenzene was synthesized according to Method
A13, Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with

25 tetrahydrofurfurylamine according to Method A13, Step 3 to give 4-(3-(iV-
(tetrahydrofurylmethyl)carbamoyI)phenoxy)-l-nitrobenzene. According to Method A13
Step 4, 4-(3-(iV-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-l-nitrobenzene was reduced
to 4-(3-(iV-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method
Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(iV-

30 (tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford the urea.

70

BAYER 18

Entry 64: 4-(3-Carboxyphenoxy)-l -nitrobenzene was synthesized according to Method
A13, Step 2. 4-(3-Carboxyphenoxy)-l -nitrobenzene was coupled with 2-aminomethyl-l-
ethyipyrrolidine according to Method A13, Step 3 to give 4-(3-(iV-((l-
methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-l-nitrobenzene. According to Method
A13 Step 4, 4-(3-(A^-((l-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-l-nitrobenzene
was reduced to 4-(3-(iV-((l-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline.
According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
with 4-(3-(A r -((l-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to afford the
urea.

Entry 65: 4-Chloro-N-methylpyridinecarboxarnide was synthesized as described in
Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according
to Method A2, Step 4 to give 4-(4-(2-(jV-methylcarbamoyl)phenylthio)aniline. According
to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-
(iV-methylcarbamoyl)phenylthio)aniline to afford the urea.

Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine
according to Method A2, Step 3b. The resulting 4-chloro-A r -isopropyl-2-
pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to
give 4-(2-(Af-isopropylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-
chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with -4-(2-(iV-
isopropylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

Entry 67: A r -(4-Chloro-3-(trifluoromethyl)phenyl-iV"-(4-ethoxycarbonylphenyi) urea was
synthesized according to Method Cle. iV-(4-Chloro-3-(trifluoromethyl)phenyl-iV"-(4-
ethoxycarbonylphenyl) urea was saponified according to Method D3 to give iV-(4-chloro-
3-(trifluoromethyl)phenyl-A ir '-(4-carboxyphenyl) urea. AT-(4-Chloro-3-

(trifluoromethyl)phenyl-A'''-(4-carboxyphenyl) urea was coupled with 3-
methylcarbamoylanihne according to Method Dlb to give N-(4-chloro-3-
(trifluoromethyl)phenyl-iV'-(4-(3-rnethylcarbamoylphenyl)carbamoylphenyl) urea.

71

BAYER 18

Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione was synthesized
according to Method A9. According to Method CI a, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-l,3-dione to afford
the urea.

5

■ Entry 69: 4-Chloro-iV-methylpyridinecarboxamide was synthesized as described in
Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according
to Method A2, Step 4 to give 3-(4-(2-(iV-methylcarbamoyl)phenylthio)amline.
According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
10 with 3-(4-(2-(A r -methylcarbamoyl)phenylthio)aniline to afford the urea.

Entry 70: 4-(2-(iV-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was

synthesized according to Method A10. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(iV-{2-morpholin-4-
15 ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea.

Entry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to
Method A14. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted
with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the
20 urea. iV-(4-Chioro-3-(trifluoromethyl)phenyl)-iV'-(4-(3-(5-
methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step
1, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the
amide. -

25 Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to
Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. jV-(5-
(Trifluoromethyl)-2-methoxyphenyl)-iV'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)
urea was saponified according to Method D4, Step 1, and the corresponding acid was

30 coupled with methylamine according to Method D4, Step 2 to afford the amide.

72

BAYER 18

Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to
Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method CI a to afford the urea. 2V-(5-
(Trifluoromethyl)-2-methoxyphenyl)-A/"-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)
5 urea was saponified according to Method D4, Step 1, and the corresponding acid was
coupled with iV.iV-dimethylethylenediamine according to Method D4, Step 2 to afford the
amide.

Entry 74: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with 2-
10 hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-iV-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-iV-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl
chloride, followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(iV-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method Cla, 4-
15 chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(A r -(2-
triisopropylsilyloxy)ethylcarbamoyl) pyridyloxyaniline to afford A^-(4-chloro-3-
((trifluoromethyl)phenyl)-A^'-(4-(4-(2-(iV-(2-triisopropylsilyloxy)
ethylcarbamoyl)pyridyloxyphenyl) urea.

20 Entry 75: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Clf to afford the urea, which
was coupled with 3-aminopyridine according to Method Die.

25 Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled
with iV-(4-acetylphenyl)piperazine according to Method Die.

30 Entry 77: '4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-

73

BAYER 18

carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled
with 4-fluoroaniJine according to Method Die.

Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifIuoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled
with 4-(dimethylamino)anihne according to Method Die.

Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled
with iV-phenylethylenedi amine according to Method Die.

Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifIuoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled
with 2-methoxyethylamine according to Method Die.

Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled
with 5-amino-2-methoxypyridine according to Method Die.

Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled
with 4-morpholinoaniline according to Method Die.

Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-

74

BAYER 18

carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled
with iV-(2-pyridyl)piperazine according to Method Die.

Entry 84: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with 2-
5 hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-/V-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-/V-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl
chloride, followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(iV-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method Cla, 4-
p 10 chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(iV-(2-
% triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give N-(4-chloro-3-

« ((trifluoromethyl)phenyl)-iV'-(4-(4-(2-(iV-(2-

m triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl) urea. The urea was deprotected

J according to Method D5 to afford A^-(4-chloro-3-((trifluoromethyl)phenyl)-iV , -(4-(4-(2-

f 15 (iY-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea.

Iji Entry 85: 4-(2-(A^Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to

Q Method A2. 4-Bromo-3-(trifluoromethyl)aniHne was converted to 4-bromo-3-

(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla,
20 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-
A methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

Entry 86: 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized
according to Method A6. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-
25 bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to
Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(iV-
methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the urea.

Entry 87: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-
30 chloro-A r -methyl-2-pyridinecarboxamide, which had been synthesized according to
Method A2, Step 3b, to give 4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline.

75

BAYER 18

4-Brotno-3-(trifluoromethyl)aniline- was converted into 4-bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a,
4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(JV-
methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.

5

Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according
to Method A2, Step 3b. The resulting 4-chloro-iV-ethyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(/V-
ethyLcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was

10 converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl.
According to Method CI a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted
with 4-(2-(7V-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

Entry 89: 4-Chloro-A^methyl-2-pyridinecarboxamide, which was synthesized according
15 to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4
to form 3-(-2-(A''-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-
(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl
isocyanate according to Method Bl. According to Method CI a, 4-bromo-3-
(trifluoromethyl)phenyl isocyanate was reacted with 3-(-2-(A^-methylcarbamoyl)-4-
20 pyridyloxy)aniline to afford the urea.

Entry 90: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-
chloro-A r -methyl-2-pyridinecarboxamide, which had been synthesized according to
Method A2, Step 3b, to give 3-(2-(iV-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline.
25 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a,
4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(iV-
methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.

30 Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine
according to Method A2, Step 3b. The resulting 4-chloro-A r ,A r -dimethyl-2-

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BAYER 18

pyridinecarboxarnide was reacted with 4-aminophenol according to Method A2, Step 4 to
give 4-(2-(N,iV-dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-
(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl
isocyanate according to Method Bl. According to Method CI a, 4-bromo-3-
5 (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(iV,A r -climethylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.

Entry 92: 4-Chloro-N-methylpyridinecarboxaniide was synthesized as described in
Method A2', Step 3b. The chloropyridine was reacted with 4-aminothiophenol according
10 to Method A2, Step 4 to give 4-(4-(2-(^V-methylcarbamoyl)phenylthio)aniline. 4-Bromo-
3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl
isocyanate according to Method Bl'. According to Method Cla, 4-bromo-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(JV-
methylcarbamoyl)phenylthio)anihne to afford the urea.

15

Entry 93: 4-Chloro-iV-methylpyridinecarboxamide was synthesized as described in
Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according
to Method A2, Step 4 to give 3-(4-(2-(A''-methylcarbamoyl)phenylthio)aniline. 4-Bromo-
3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl
20 • isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-
(trifluoromethyl)phenyl ' isocyanate was reacted with 3-(4-(2-{iV-
methylcarbamoyl)phenylthio)aniline to afford the urea.

Entry 94: 4-(2-(A r -(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was

25 synthesized according to Method A10. 4-Bromo-3-(trifluoromethyl)aniline was
converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl.
According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted
with 4-(2-(/V-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea.

30 Entry 95: 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to
Method A2. 4-Chloro-2-methoxy-5-(trifIuoromethyl)aniline was synthesized according

77

BAYER 18

to Method A7. 4-Chloro-2-methoxy-5-(trifiuorornethyl)aniline was converted into 4-
chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl.
According to Method CI a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was
reacted with 4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

Entry 96: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized
according to Method A6. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was
synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according
to Method Bl. According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(//-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline
afford the urea.

Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-
chloro-iV-methyl-2-pyridinecarboxamide, which had been synthesized according to
Method A2, Step 3b, to give 4-(2-(A^-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline.
4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7.

4- Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-

5- (trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method
Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(iV-
methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.

Entry 98: 4-Chloro-A r -methyl-2-pyridinecarboxamide, which was synthesized according
to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4
to form 3-(-2-(A r -methyIcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-
(trifluoromethyi)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-
5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla,
4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate as was reacted with 3-(-2-(iV-
methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

78

BAYER 18

Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according
to Method A2, Step 3b. The resulting 4-chloro-iV-ethyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(iV-
ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
5 was, synthesized according to Method A7. 4-Chloro-2-methoxy-5-
(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla,

4- chloro-2-methoxy-5-(tafluoromethyl)phenyl isocyanate was reacted with 4-(2-(iV-
~ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

10

Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine
according to Method A2, Step 3b. The resulting 4-chloro-A r ,iV-dimethyl-2-
pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to
give 4-(2-(//,A^-dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-
15 (trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-

5- (trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla,
4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N,N-
dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

20

Entry 101: 4-Chloro-iV-methyl-2-pyridinecarboxamide, which was synthesized according
to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4
to form 3-(-2-(/V-methylcarbamoyl)-4-pyridyloxy)aniline. 2-Amino-3-
methoxynaphthalene was synthesized as described Method Al. According to Method
25 C3, 2-amino-3-methoxynaphthalene was reacted with bis(trichloromethyl) carbonate
followed by 3-(-2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline to form the urea.

Entry 102: 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according
to Method A2. 5-ferr-Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized according to
30 Method A4. 5-r«rr-Butyl-2-(2,5-dimethylpyrrolyl)anihne was reacted with CDI followed

79

BAYER 18

by 4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)amline according to Method C2d to afford
the urea.

Entry 103: 4-Chloro-A r -methyl-2-pyridinecarboxamide was synthesized according to
Method A2, Step 3b. 4-Chloro-iV-niethyl-2-pyridinecarboxamide was reacted with 4-
aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-
(2-(iY-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-
amino-2-methoxyquinoline with CDI followed by 4-(2-(A r -methylcarbamoyl)-4-
pyridyloxy)aniline afforded bis,(4-(2-(^V-methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.

Listed in the Tables below are compounds which have been synthesized
according to the Detailed Experimental Procedures given above:

Tables

The compounds listed in Tables 1-6 below were synthesized according to the general
methods shown above, and the more detailed exemplary procedures are in the entry
listings above and characterizations are indicated in the tables.
Table 1. 3-tert-Butylphenyl Ureas

H H

Entry

R

mp
(°C)

HPLC
(min.)

TLC
IV

TLC
Solvent
System

Mass
Spec.
[Source]

Synth.
Method

1

o

V-nh

0.22

50%
EtOAc
/50%
hexane

418

(M+H)+

(HPLC

ES-MS)

A13
C3

80

BAYER 18

2

0 58

50%
EtOAc
/50%
hexane

401

(M+H)+

(HPLC

ES-MS)

All

C3

D

o

V-nh

133-
135

0.68

100%
EtOAc

448

(M+H)+
(FAB)

A8
C2d

Table 2. 5-terr-Butyl-2-methoxyphenyl Ureas

Entry

R

mp
(°C)

HPLC

(min.)

TL

CR f

TLC
Solvent
System

Mass
Spec.
[Source]

Synth.
Method

4

O

5.93

448

(M+H)+

(HPLC

ES-MS)

A13

Bl

Cla

5

o

120-
122

0.67

100%
EtOAc

478

(M+H)+
(FAB)

A8
C2d

6

0.40

50%
EtOAc
/50%
hexane

460

(M+H)+

(HPLC

ES-MS)

A3
C2d

7

0.79

50%
EtOAc
/50%
hexane

446

(M+H)+

(HPLC

ES-MS)

A12
C2d

81

BAYER 18

Table 3.

5- (Trifluoromethyl)-2-methoxyphenyl Ureas

0

H

OMe

Entry

R

mp

(°C)

(min.)

TT C

Rf

TLC
oolvent
System

Mass
opec.
[Source]

Synth.
Method

8-

0

y— nh

r, — ^ r=\ Me

250
(dec)

460

(M+H)+

A13
C2a

9

^=H Me

206-
208

0.54

10%
MeOH/

y\)70

CH2C12

446

(M+H)+
ES-MS)

A3 step
?

j

Ao step
4,

Bl,
Cla

10

f/ — \\ P

-CHH

0.33

50%
EtOAc/
50% pet
ether

445

(M+H)+

(HPLC

ES-MS)

A13
C3

11

— e V V— NH
\={ /=( Me

0.20

2%
Et3N/
98%
EtOAc

461

(M+H)+

(HPLC

ES-MS)

A2
C4

12

-hQ Vnh 2

0.27

1%

Et3N/

99%

EtOAc

447

(M+H)+

(HPLC

ES-MS)

A2
C4

13

o

V-NH

0.62

100%
EtOAc

461

(M+H)+
(FAB)

A2
C2a

14

o

114-
117

0.40

1%

Et3N/

99%

EtOAc

447

(M+H)+
(FAB)

A2
C4

82.

BAYER 18

15

0

V-NH

^ — ^ /^K Me

232-
235

0.54

100%
EtOAc

490

(M+H)+
(tA.d)

A8
C2d

16

0

Me /— NH

210-

213

0.29

5%

MeOH/

45 %

EtOAc/
50% pet
ether

475

(M+H)+

/ rr o r c

(rirLL.
ES-MS)

A5'

Bl

Clc

17

0

CI V-NH

187-
188

0.17

50%
EtOAc/
50% pet
ether

495

(M+H)+

(HPLC

ES-MS)

A6
Bl
Cla

18

— ^~^>— Me ^ — NH 2

0.48

100%
EtOAc

475

(M+H)+

(rirjLC

ES-MS)

A2 step

4,

ril

Cla

19

o

V-NH

194-
196

0.31

5%

MeOH/
45%
EtOAc/
50% pet
ether

475

(M+H)+

(HPLC

ES-MS)

A2
Bl
Cla

20

o

CI V-NH

214-
216

0.25

5%

MeOH/
45%
EtOAc/
50% pet
ether

495

(M+H)+

(HPLC

ES-MS)

A2
Cla

21

Q

AO

208-
210

O.jO

50%
EtOAc/
50%
hexane

481

(M+H)+

(HPLC

ES-MS)

ATA

Aiy

C2a

22

o

V-NH 2

188-
190

0.30

70%
EtOAc/
50%
hexane

447

(M+H)+

(HPLC

ES-MS)

A15,
step 4,
Cla

23

0

0.50

70%
EtOAc/
30%
hexane

472

(M+H)+
(FAB)

A3
Bl
Cla

83

BAYER 18

24

0 Me

Vn

203-
205

0.13

100%
EtOAc

479

(M+H)+

(HPLC

ES-MS)

A2
Bl
Cla

25

r°

MH

0.09

75%
EtOAc/
25%
hexane

458

(M+H)+

(HPLC

ES-MS)

A12
C2d

26

MeO

x=/ ^—^ Me

169-
171

0.67

50%
EtOAc/
50% pet
ether

474

(M+H)+

(HPLC

ES-MS)

A13

stepl,

A13

step 4,

A16,

Bl

Cla

27

O

^ — NH

218-
219

0.40

50%
EtOAc/
50% pet
ether

477

(M+H)+

(HPLC

ES-MS)

A2 step
3b,

A2 step
4,
Bl,
Cla

28

o

-JMe

212-
214

0.30

40%
EtOAc/
60%
hexane

A9
Bl
Cla

29

0.33

50%
EtOAc/
50% pet
ether

474

(M+H)+

(HPLC

ES-MS)

A2 step
3b,

A2 step
4,
Bl,
Cla

30

o

V-NH

210-

"71 1

A2

Jj I

Cla

31

0

V-NH

b

210-
204

0.43

10%

MeOH/

CH2C12

A14
Bl
Cla
D4

32

o

V-NH

247-
249

•0.57

10%

MeOH/

CH2C12

A14
Bl
Cla
D4

84

BAYER IS

00

0.

^" 0 ^} Me'""

217-
219

0.07

10%

MeOH/

CH2C12

A14
Bl
Cla
D4

34

o

V-NH

0.11

70%
EtOAc/
30%
hexane

All
Bl
Clf
Die

35

Q
O

^ — N

0.38

70%
EtOAc/
30%
hexane

All
Bl

Clf
Die

36

F — \ V-NH

\=/ >=0

. -

0.77

70%
EtOAc/
30%
hexane

All
Bl
Clf
Die

37

N — ( V-NH
Me \=/ V=0

0.58

70%
EtOAc/
30%
hexane

All
Bl
Clf
Die

38

MeO-^ ~y~NH

-CXT

0.58

70%
EtOAc/
30%
hexane

All
Bl
Clf
Die

39

0 N — (f V-NH

\ / W v= 0

0.17

70%
EtOAc/
30%
hexane

All
Bl
Clf
Die

40

0- N C N -O-T 0

0.21

70%
EtOAc/
30%
hexane

All
Bl
Clf
Die

85

BAYER 13

Table 4.

3-(Trifluoromethyl)-4-chlorophenyl Ureas

0

H

CI

Entry

R

mp

(°C)

HPLC
(min.)

TLC

K F

TLC
Solvent
System

Mass
Spec.
[Source]

Synth.
Method

41

0

/— NH

163-

lOJ

0.08

50%
EtOAc/
50% pet
ether

464

(M+H)+

(HPLC

ES-MS)

A13
C3

42

o

/ — NH

215

0.06

50%
EtOAc/
50% pet
ether

465

(M+H)+

(HPLC

ES-MS)

A2
Cla

43

O

y — NH„

0.10

50%
EtOAc/
50% pet
ether

451

(M+H)+

(HPLC

ES-MS)

A2
Cla

44

0.25

30%
EtOAc/
70% pet
ether

451

(M+H)+

(HPLC

ES-MS)

A2
Cla

45

/==( Me
0— \v N

0.31

30%
EtOAc/
70% pet
ether

465

(M+H)+

(HPLC

ES-MS)

A2
Cla

46

V NH

0

176-
179

0.23

40%
EtOAc/
60%
hexane

476

(M+H)+
(FAB)

A3
Cla

47

o

Me V-NH

0.29

5%

MeOH/
45%
EtOAc/
50% pet
ether

478

(M+H)+

(HPLC

ES-MS)

A5
Clc

48

"S-NH

"OK} ■*

206-
209

A15
Cla

86

BAYER 18

49

0

CI y — NH

147-
151

0.22

50%
EtOAc/
50% pet
ether

499

(M+H)+

(HPLC

ES-MS)

Cla

50

— <? V-Me V-NH
X ={ /=( Me

0.54

100%
EtOAc

479

(M+H)+

(HPLC

ES-MS)

A2
Cla

51

0

V-NH

187-
189

0.33

5%

MeOH/
45%
EtOAc/
50% pet
ether

479

(M+H)+

(HPLC

ES-MS)

A2
Cla

52

0

CI V-NH

219

0.18

5%

MeOH/
45%
EtOAc/
50% pet
ether

499

(M+H)+

(HPLC

ES-MS)

A2
Cla

53

246-
248

0.30

50%
EtOAc/
50%
hexane

485

(M+H)+

(HPLC

ES-MS)

A19,
Cla

0
Me

196-
200

0.30

70%
EtOAc/
30%
hexane)

502

(M+H)+

(HPLC

ES-MS)

A15
Cla

55

228-
230

0.30 '

30%
EtOAc/
70%
CH2C12

466

(M+H)+

(HPLC

ES-MS)

56

x=/ N — y NH
Me 7

238-
245

57

o

221-
222

0.75

80%
EtOAc/
20%
hexane

492

(M+H)+
(FAB)

Cld
Dla

58

o

V-NH

247

0.35

100%
EtOAc

Cld
Dla
D2

87

BAYER IS

59

O Me

1QQ

200

u.uy

100%
EtOAc

479

(M+H)+

(HPLC

ES-MS)

A2
Cla

60

MeO

158-

1 £ A
J.DU

0.64

50%
EtOAc/
50% pet
ether

61

0

— NH
f == \ ^ \

-0-°-0 A\

^0

195-
197

0.39

10%
MeOH/
CH2C1
2

A13
Cla

Liil

62

0

J — NH

^>°<)

170-

1 /Z

0.52

10%
MeOH/
CH2C1
2

A13
Cla

£ -

63

O

V NH 0^

-O-o-Q ^°

168-
171

u. Dy

iu/o
MeOH/
CH2C1
2

AIT
AID

Cla

s

64

O Et

176
i / u-

177

U.J J

11/70

MeOH/
CH2C1
2

A1j
Cla

65

o

-o-o Me

1 J>U-

133

45 /

(M+H)+

(HPLC

ES-MS)

A2
Bl
Cla

66

0

V-NH

-CM) ' PN

AZ

Cla

67

o

V-NH

225-
229

0.23

100%
EtOAc

Cle

D3

Dlb

68

0

234-
236

0.29

40%
EtOAc/
60%
hexane

A9
Cla

88

BAYER 18

69

^ /==< Me
S -\_/

0.48

50%
FtOAr/
50% pet
ether

481

(HPLC
ES-MS)

70

0

>-NH

0.46

5%

MeOH/

JJ /o

CH2C12

564

(M+H)+
ES-MS)

A10
Cla

71

0

N — 0

199-
201

0.50

10%
MeOH/
CH2C1
2

A14
Cla
D4

72

235-
237

0.55

10%
MeOH/
CH2C1
2

A14
Cla
D4

73

o

V-NH

~^y°-\^ ^ Vl-Me
— N Me

zuu-
201

0.21

50%
MeOH/
CH2C1
2

A14
Cla
D4

74

o

v — MM

— <f V°-<\^ > OSi(Pr-i) 3

145-
148

75

</ Vnh
w _>=0

-o-o

0.12

70%
EtOAc/
30%
hexane

527

(M+H)+

(HPLC

ES-MS)

All
Clf
Die

76

0

Me— V

Q

o

— N

0.18

70%
EtOAc/
30%
hexane

All
Clf

D1 r

89

BAYER 18

77

F— <f V-NH

0.74

70%
EtOAc/
30%
hexane

All
Clf
Die

78

N— f V-NH
Me >=0

0.58

70%
EtOAc/
30%
hexane

All
Clf
Die

79

0

V-NH

<f /— 0— ^ /> NH

0.47

70%
EtOAc/
30%
hexane

569

(M+H)+

(HPLC

ES-MS)

All
Clf
Die

80

0

y — nh

/-a V

0.18

70%
EtOAc/
30%
hexane

508

(M+H)+

(HPLC

ES-MS)

All
Cli
Die

81

MeO-^ V-NH

0.58

70%
EtOAc/
30%
hexane

557

(M+H)+

(HPLC

ES-MS)

All
Clf
Die

82

0 N— <f V-NH
W W

0.37

70%
EtOAc/
30%
hexane

611

(M+H)+

(HPLC

ES-MS)

All
Clf
Die

si

OJ

o

N — N

rj in

u.iy

10 70

EtOAc/

30%

hexane

All
All

Clf
Die

84

o

V-NH

-Q-o-Qi oh

179-
183

A2
A17
Cla
D5

90

BAYER 18

Table 5. 3-(Trifluoromethyl)-4-bromophenyl Ureas

fXf

H H

Entry

R

mp

HPLC

( TTtlTI ^

^lmii.j

TLC

TLC
Solvent

Mass
Spec.

1 \ An tv* o f

Synth..
jyieuiOu

85

0

V-NH

186-
187

0.13

50%
EtOAc/
50% pet
ether

509

(M+H)+

(HPLC

ES-MS1

A2
Bl
Cla

86

o

CI >-NH
\ — / v a

150-
152

0.31

50%
EtOAc/
50% pet

prVi pt*

545 .

(M+H)+

(HPLC

A6
Bl
Cla

87

o

CI V-NH

217-
219

0.16

50%
EtOAc/
50% pet
ether

545

(M+H)+

(HPLC

ES-MS)

A2
Bl
Cla

88

o

V-'NH

183-
184

0.31

50%
EtOAc/
50% pet
ether

525

(M+H)+

(HPLC

ES-MS)

A2
Bl
Cla

89

-TX Vnh

' r={ Me

0.21

50%
EtOAc/
50% pet
ether

511

(M+H)+

(HPLC

ES-MS)

A2
Bl
Cla

90

— V-Me V-NH
\={ Me

0.28

50%
EtOAc/
50% pet
ether

525

(M+H)+

(HPLC

ES-MS)

A2
Bl
Cla

91

O Me

214-
216

0.28

50%
EtOAc/
50% pet
ether

522

(M+H)+

(HPLC

ES-MS)

A2
Bl
Cla

91

BAYER 18

92

0
>-NH

0.47

50%
EtOAc/
50% pet
ether

527

(M+H)+

(HPLC

ES-MS)

A2 step
3b,

A2 step
4,
Bl,
Cla

93

y=( Me

S ~V/ J

0.46

50%
EtOAc/
50% pet

f^frH AT*
CU1C1

527

(M+H)+
(HPLC

CO -1VJ.O J

A2 step
3b,

A2 step

A

Bl,
Cla

94

0

V-NH

\— 0

ms-
iso

0.41

5%

MeOH/

95%

CH2C12

A10

Bl

Cla

92

BAYER 18

Table 6.

5-(Trifluoromethyl)-4-chloro-2-methoxyphenyl Ureas

OMe

Entry

R

mp

(°C)

HPLC
(min.)

TLC

Rf

TLC
Solvent
System

Mass
Spec.
[Source]

Synth.
Method

95

0

V-NH

140-
144

0.29

5%

MeOH/
45%
EtOAc/
50% pet
ether

495

(M+H)+

(HPLC

ES-MS)

A2
A7
Bl
Cla

96

o

C! V-NH

244-
245

0.39

5%

MeOH/
45%
EtOAc/
50% pet
ether

529

(M+H)+

(HPLC

ES-MS)

A6
A7
Bl
Cla

97

o

CI y-NH

220-
221

0.25

5%

MeOH/
45% -
EtOAc/
50% pet
ether

529

(M+H)+

(HPLC

ES-MS)

A2
A7
Bl
Cla

98

°-\_/<

0.27

5%

MeOH/
45%
EtOAc/
50% pet
ether

495

(M+H)+

(HPLC

ES-MS)

A2
A7
Bl
Cla

99

. o

180-
181

0.52

5%

MeOH/
45%
EtOAc/
50% pet
ether

509

(M+H)+

(HPLC

ES-MS)

A2
A7
Bl
Cla

100

o

>-NH

162-
165

A2
A7
Bl
Cla

93

BAYER 18

Table 7.

Additional Ureas

Entry

R

mp

(°C\

HPLC

TLC

TLC
Solvent
System

Mass
Spec.
[Source]

Synth.

TV if — J

Method

101

(Pi °

OMe H H

162-
165

Al
A2
C3

102

M H H

0.10

50%
EtOAc/
50%
hexane

442

(M+H)+

(HPLC

ES-MS)

A2
A4
C2d

103

O

x

HN NH

0 6

O 0
NH-Me Me— NH

125-
130

0.24

40%
EtOAc/
60%
hexane

512

(M+H)+
(FAB)

A2
C2b

BIOLOGICAL EXAMPLES

10 In Vitro raf Kinase Assay :

In an in vitro kinase assay, raf was incubated with MEK in 20 mM Tris-HCl, pH 8.2
containing 2 mM 2-mercaptoethanol and 100 mM NaCl. This protein solution (20 uL)
was mixed with water (5 uL) or with compounds diluted with distilled water from 10 mM
stock solutions of compounds dissolved in DMSO. The kinase reaction was initiated by

15 adding 25 uL [X- 33 P]ATP (1000-3000 dpm/pmol) in 80 mM Tris-HCl, pH 7.5, 120 mM
NaCl, 1.6 mM DTT, 16 mM MgCl 2 . The reaction mixtures were incubated at 32 °C,
usually for 22 min. Incorporation of 33 P into protein was assayed by harvesting the
reaction onto phosphocellulose mats, washing away free counts with a 1% phosphoric

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acid solution and quantitating phosphorylation by liquid scintillation counting. For high
throughput screening, 10 uM ATP and 0.4 uM MEK was used. In some experiments, the
kinase reaction was stopped by adding an equal amount of Laemmli sample buffer.
Samples were boiled 3 min and the proteins resolved by electrophoresis on 7.5%
5 Laemmli gels. Gels were fixed, dried and exposed to an imaging plate (Fuji).
Phosphorylation was analyzed using a Fujix Bio-Imaging Analyzer System.

All compounds exemplified displayed IC50S of between 1 nM and 10- uM.

10 Cellular Assay :

For in vitro growth assay, human tumor cell lines, including but not limited to HCT116
and DLD-1, containing mutated K-ras genes were used in standard proliferation assays
for anchorage dependent growth on plastic or anchorage independent growth in soft
agar. Human tumor cell lines were obtained from ATCC (Rockville MD) and maintained

15 in RPMI with 10% heat inactivated fetal bovine serum and 200 mM glutamine. Cell
culture media and additives were obtained from Gibco/BRL (Gaithersburg, MD) except
for fetal bovine serum (JRH Biosciences, Lenexa, KS). In a standard proliferation assay
for anchorage dependent growth, 3 X 10 J cells were seeded into 96-well tissue culture
plates and allowed to attach overnight at 37 °C in a 5% C0 2 incubator. Compounds were

20 titrated in media in dilution series and added to 96-well cell cultures. Cells were allowed
to grow 5 days typically with a feeding of fresh compound containing media on day
three. Proliferation was monitored by measuring metabolic activity with standard XTT
colorimetric assay (Boehringer Mannheim) measured by standard ELISA plate reader at
OD 490/560, or by measuring 3 H-thymidine incorporation into DNA following an 8 h

25 culture with 1 uCu 3 H-thymidine, harvesting the cells onto glass fiber mats using a cell
harvester and measuring J H-thymidine incorporation by liquid scintillant counting.

For anchorage independent cell growth, cells were plated at 1 x 10 3 to 3 x 10 3 in 0.4%
Seaplaque agarose in RPMI complete media, overlaying a bottom layer containing only
30 0.64% agar in RPMI complete media in 24-welI tissue culture plates. Complete media
plus dilution series of compounds were added to wells and incubated at 37 °C in a 5%

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CO2 incubator for 10-14 days with repeated feedings of fresh media containing
compound at 3-4 day intervals. Colony formation was monitored and total cell mass,
average colony size and number of colonies were quantitated using image capture
technology and image analysis software , (Image Pro Plus, media Cybernetics).

5

In Vivo Assay :

An'z'n vivo assay of the inhibitory effect of the compounds on tumors (e.g., solid cancers),
mediated by raf kinase can be performed as follows:

10 CDI nu/nu mice (6-8 weeks old) are injected subcutaneously into the flank at 1 x 10 6 cells
with human colon adenocarcinoma cell line. The mice are dosed i.p., i.v. or p.o. at 10,
30, 100, or 300 mg/Kg beginning on approximately day 10, when tumor size is between
50-100 mg. Animals are dosed for 14 consecutive days once a day; tumor size was
monitored with calipers twice a week.

15

The inhibitory effect of the compounds on raf kinase and therefore on tumors (e.g., solid
cancers) mediated by raf kinase can further be demonstrated in vivo according to the
technique of Monia et al. {Nat. Med. 1996, 2, 668-75).

20

The preceding examples can be repeated with similar success by substituting the
generically or specifically described reactants and/or operating conditions of this
invention for those used in the preceding examples.

25 From the foregoing description, one skilled in the art can easily ascertain the essential
characteristics of this invention and, without departing from the spirit and scope thereof,
can make various changes and modifications of the invention to adapt it to various usages
and conditions.

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